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EP2507238B1 - Diphenyl-pyrazolopyridine compounds, their preparation and their application as modulators of the nuclear receptor not - Google Patents

Diphenyl-pyrazolopyridine compounds, their preparation and their application as modulators of the nuclear receptor not Download PDF

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Publication number
EP2507238B1
EP2507238B1 EP10801625.4A EP10801625A EP2507238B1 EP 2507238 B1 EP2507238 B1 EP 2507238B1 EP 10801625 A EP10801625 A EP 10801625A EP 2507238 B1 EP2507238 B1 EP 2507238B1
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Prior art keywords
pyridin
pyrazolo
group
fluorophenyl
methylbenzamide
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German (de)
French (fr)
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EP2507238A1 (en
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Florian Auger
Luc Even
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Sanofi SA
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Sanofi SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to diphenyl-pyrazolopyridine derivatives, to their preparation and to their therapeutic application in the treatment or prevention of diseases involving the nuclear Nurr-1 receptors, also called NR4A2, NOT, TTNUR, RNR-1, and HZF3.
  • the compounds of formula (I) may comprise one or more asymmetric carbon atoms. They can therefore exist as enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including racemic mixtures, form part of the invention.
  • the compounds of formula (I) may exist in the form of bases or addition salts with acids. Such addition salts are part of the invention.
  • salts can be prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for the purification or the isolation of the compounds of formula (I) are also part of the invention.
  • the compounds of formula (I) may also exist in the form of hydrates or solvates, namely in the form of associations or combinations with one or more molecules of water or with a solvent. Such hydrates and solvates are also part of the invention.
  • the compounds of general formula (I) can be prepared according to the process described in scheme 1.
  • the compounds of the general formula (Ia), in which R 1 represents OR 4, R 4 represents an alkyl group ALK, R represents a hydrogen atom, X and Y are defined as above, can be prepared by a reaction of metal-catalyzed coupling, such as palladium, between a compound of general formula (II) in which R represents a hydrogen atom, X is defined as above and Hal represents a halogen atom, and a derivative of formula general (III) wherein Y and ALK are defined as above, and Z represents a boron derivative.
  • metal-catalyzed coupling such as palladium
  • route A the compounds of general formula (Ic) in which R 1 represents NR 2 R 3, R represents a hydrogen atom and X, Y, R 2 and R 3 are defined as above, by a coupling reaction, catalyzed by a metal such as palladium, between a compound of general formula (II) in which R represents a hydrogen atom, X is defined as above and Hal represents an atom of halogen and a derivative of general formula (IV) wherein Y, R2 and R3 are defined as above and Z represents a boron derivative.
  • route B the compounds of general formula (Ic) in which R 1 represents NR 2 R 3, R represents a hydrogen atom and X, Y, R 2 and R 3 are defined as above, can be prepared by a reaction between a compound of general formula (Ia), wherein R1 represents OR4, R4 represents an alkyl group ALK, R represents a hydrogen atom, X, Y are defined as above, and an amine of general formula (V) in which R2 and R3 are defined as above, in the presence of trimethylaluminum in solution or complexed with a tertiary amine such as DABCO according to the method described by D. Glynn, D. Bernier, S. Woodward in Tetrahedron Letters, 2008, 49, 5687-5688 .
  • route C the compounds of general formula (Ic) in which R 1 represents NR 2 R 3, R represents a hydrogen atom and X, Y, R 2 and R 3 are defined as previously by a reaction between a compound of general formula (Ib), wherein R1 represents OR4, R represents a hydrogen atom, X and Y are defined as above and R4 represents a hydrogen atom, and an amine of general formula (V) in which R2 and R3 are defined as above, in the presence of an acid activator such as isobutyl chloroformate.
  • R1 represents OR4
  • R represents a hydrogen atom
  • X and Y are defined as above
  • R4 represents a hydrogen atom
  • an acid activator such as isobutyl chloroformate
  • route D the compounds of general formula (Ic) in which R 1 represents NR 2 R 3, R represents a hydrogen atom and X, Y, R 2 and R 3 are defined as above by a catalyzed coupling reaction can be prepared. by a metal such as palladium, between a compound of general formula (VI) in which R represents a hydrogen atom, X is defined as above and Z represents a boron derivative and a derivative of general formula (VII) in which Y, R2 and R3 are defined as above and Hal. represents a halogen atom.
  • a metal such as palladium
  • the compounds of general formula (Ic) in which R 1 represents NH 2, R represents a hydrogen atom and X and Y are defined as above can be obtained by hydrolysis of the nitriles of general formula (IX), by example using oxygenated water in the presence of base.
  • the compounds of general formula (IX) can be obtained by a metal-catalyzed coupling reaction such as palladium between a compound of general formula (II) in which R represents a hydrogen atom, X is defined such that previously and Hal represents a halogen atom and a derivative of general formula (VIII) wherein Y is defined as above, CN represents a cyano group and Z represents a boron derivative.
  • the compounds of general formula (I) can be prepared according to the process described in scheme 3.
  • the compounds of general formula (Id) in which X, Y and R 1 are defined as above and R represents a Hal halogen atom by electrophilic halogenation of compounds (Ia) or (Ic), can be prepared by example by chlorination, using an agent such as N- chlorosuccinimide.
  • the compounds of general formula (II) and (VI) can be prepared according to the process described in scheme 4.
  • the compounds of general formula (II) wherein X is defined as above, R represents a hydrogen atom and Hal represents a halogen atom can be prepared by the action of O- (mesitylenesulfonyl) hydroxylamine (MSH) on a compound of general formula (XIII) in which X and Hal are defined as above, for example according to the method described by Y. Tamura, J.-H. Kim, Y. Miki, H. Hayashi, M. Ikeda, in J.Het. Chem., 1975, 12, 481 .
  • route B the compounds of general formula (II) in which X is defined as above, R represents a hydrogen atom and Hal represents a halogen atom by conversion of the compounds of general formula ( XIII) in compounds of general formula (XIV) in which X and Hal are defined as above, by the action of an acid anhydride such as trifluoroacetic anhydride in the presence of a base such as triethylamine, and then cyclization to compounds of general formula (II) in the presence of a catalyst such as ferrous chloride, for example according to the method described by KS Gudmundsson in Bioorg. Med. Chem., 2005, 13, 5346 .
  • a catalyst such as ferrous chloride
  • Compounds (XIII) can be obtained from compounds (XII) by the action of hydroxylamine.
  • the compounds (XII) can be obtained from picolines of general formula (X) and esters of general formula (XI) in which X is defined as above and ALK represents an alkyl group, in the presence of a strong base, by example according to the method described by KS Gudmundsson in Bioorg. Med Chem., 2005, 13, 5346 .
  • the compounds (VI) in which Z represents a boron derivative according to Scheme 3 can be prepared by a coupling reaction, for example of bis (pinacolato) diborone, on the compounds (II), catalyzed by a metal such as palladium according to the method described by EF DiMauro, R.Vitullo, J.Org.Chem., 2006, 71 (10), 3959 .
  • the invention also relates to the compound of formula (VI-1). This compound is useful as an intermediate for the synthesis of the compounds of formula (I).
  • the medium is then diluted with 250 mL of ethyl acetate and 100 mL of water.
  • the organic phase is separated, the aqueous phase is extracted twice with 100 ml of ethyl acetate.
  • the organic phases are then combined, dried over sodium sulphate and filtered. 15 g of silica are then added to the filtrate, concentrated under reduced pressure.
  • the powder obtained is used as a solid deposit for chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (9/1). 8.4 g (93%) of compound are obtained in the form of a yellow powder.
  • the medium is brought to room temperature and diluted with 30 ml of dichloromethane and 30 ml of water.
  • the biphasic medium is filtered on a hydrophobic cartridge (liquid / liquid extraction column 70 ml, Radleys®) and then the filtrate is concentrated under reduced pressure: the residue obtained is chromatographed on silica gel, eluting with a mixture of cyclohexane and acetate of ethyl (8/2). 0.200 g (72%) of expected compound is obtained in the form of a beige powder.
  • the medium is then heated at 90 ° C. for 3 hours before being cooled to 0 ° C.
  • the medium is then hydrolysed by dropwise addition of 10 ml of a solution of hydrochloric acid (1N). After the addition, the medium is brought to ambient temperature and then diluted with 60 ml of dichloromethane and 60 ml of water.
  • the pH of the aqueous phase is brought to 11 with a sodium hydroxide solution (1N) and the biphasic medium obtained on sintered glass filled with Celite is then filtered.
  • the filtrate is recovered and passed through a hydrophobic cartridge (liquid / liquid extraction column 70 ml, Radleys®). The filtrate is recovered and concentrated under reduced pressure after adding 1.2 g of silica.
  • the residue obtained is chromatographed on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (3/7).
  • Example 3 The procedure described in Example 3 is carried out starting from 0.200 g (0.55 mmol) of 3- [2- (4-chlorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] benzoate. of methyl obtained in step 3.1, 0.900 mL (1.80 mmol) of a solution of methylamine (2M in tetrahydrofuran) and 0.900 mL (1.80 mmol) of a solution of trimethylaluminum (2M in toluene) in 8 mL of toluene.
  • the medium is then diluted with 250 ml of ethyl acetate and 100 ml of water.
  • the organic phase is separated, the aqueous phase is extracted twice with 100 ml of ethyl acetate.
  • the organic phases are then combined, dried over sodium sulphate and filtered. 15 g of silica are then added to the filtrate, the mixture is stirred and then concentrated under reduced pressure.
  • the powder obtained is used as a solid deposit for chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (9/1). 7.5 g (88%) of compound are obtained in the form of a yellow powder.
  • the biphasic medium is stirred and decanted.
  • the organic phase is separated, and then the aqueous phase is extracted 4 times with 200 mL of dichloromethane.
  • the organic phases are then combined, dried over sodium sulphate and filtered. 15 g of silica are then added to the filtrate and then concentrated under reduced pressure.
  • the powder obtained is used as a solid deposit for chromatography on silica gel with a mixture of cyclohexane and dichloromethane (1/1) as eluent. 5.06 g (68%) of compound are obtained in the form of a white cottony powder.
  • a stream of nitrogen is charged with 0.400 g (1.37 mmol) of 5-bromo-2- (4-fluorophenyl) pyrazolo [1,5- a ] pyridine obtained in step 5.3., 0.300 g (1.67 g) mmol) of 3-methoxycarbonylphenylboronic acid, 1.330 g (4.08 mmol) of cesium carbonate in 5 ml of a 9/1 mixture of tetrahydrofuran and water. 0.11 g (0.13 mmol) of [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) are added and the medium is heated at 70 ° C. for 4 hours.
  • the medium is then brought to ambient temperature and then diluted with 40 ml of dichloromethane and 40 ml of water.
  • the medium is then filtered on a hydrophobic cartridge (liquid / liquid extraction column 70 ml, Radleys®), the organic phase is recovered and concentrated under reduced pressure after adding 2 g of silica.
  • the residue by chromatography on silica gel eluting with a mixture of cyclohexane and ethyl acetate (9/1). 0.340 g (71%) of expected product is obtained in the form of a white powder.
  • the medium is stirred overnight at room temperature and then 0.5 ml (1 mmol) of methylamine solution are added and the mixture is stirred overnight.
  • the medium is then concentrated under reduced pressure and then 5 ml of dichloromethane and 0.390 ml (2.99 mmol) of isobutyl chloroformate are added to the medium.
  • the medium is again stirred overnight before being diluted with 7 mL of dichloromethane and 7 mL of water.
  • the medium is then filtered on a hydrophobic cartridge (liquid / liquid extraction column 70 ml, Radleys®). The organic phase is recovered and concentrated under reduced pressure.
  • the medium is stirred at 60 ° C overnight.
  • the medium is then diluted with 50 ml of dichloromethane and 50 ml of water.
  • the biphasic medium is then filtered on hydrophobic cartridge (Liquid / liquid extraction column 70 mL, Radleys®).
  • the organic phase is recovered and concentrated under reduced pressure after adding 1.5 g of silica.
  • the residue obtained is chromatographed on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1/1).
  • 0.0382 g (0.67 mmol) of cyclopropylamine are diluted with 10 mL of anhydrous tetrahydrofuran.
  • 0.0859 g (0.33 mmol) of DABAL (double adduct of trimethylaluminium with 1,4-diazabicyclo [2.2.2] octane) are then gradually added before stirring the medium for 1 hour.
  • 0.145 g (0.42 mmol) of methyl 3- [2- (4-fluorophenyl) pyrazolo [1,5-a] pyridin-5-yl] benzoate obtained according to the protocol 5.4 are then added before irradiating the medium. Reaction in a microwave 2 times 30 minutes at 130 ° C.
  • the medium is then hydrolysed at about 5 ° C. using 5 ml of water and 5 ml of an aqueous solution of hydrochloric acid (1N). After the hydrolysis, the medium is diluted with 50 ml of water and 50 ml of dichloromethane and then filtered on a hydrophobic cartridge (liquid / liquid extraction column 70 ml, Radleys®). The organic phase is recovered and concentrated under reduced pressure after adding 1.5 g of silica. The residue obtained is chromatographed on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (6/4).
  • the medium is then diluted with 50 ml of water and 50 ml of dichloromethane.
  • the biphasic medium is then filtered on a hydrophobic cartridge (liquid / liquid extraction column 70 ml, Radleys®).
  • the organic phase is recovered and concentrated under reduced pressure after adding 1 g of silica.
  • the residue obtained is chromatographed on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (6/4).
  • the medium is then diluted with 200 mL of ethyl acetate and 200 mL of water.
  • the organic phase is separated, dried over sodium sulfate and filtered. 5 g of silica are then added to the filtrate before being concentrated under reduced pressure.
  • the powder obtained is used as a solid deposit for chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (95/5) to give 1.03 g (61%) of compound in the form of a yellow powder.
  • LC-MS: M + H 290
  • the organic phase is recovered and the aqueous phase is extracted with 2 times 100 ml of ethyl acetate.
  • the organic phases are then combined, dried over sodium sulfate and then concentrated under reduced pressure after adding 10 g of silica.
  • the residue obtained is chromatographed on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (8/2).
  • 0.150 g (0.52 mmol) of 5-bromo-2-p-tolylpyrazolo [1,5- a ] pyridine obtained in step 13.3 are placed, 0.136 g (0.52 mmol) of N- methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzamide obtained in step 13.4, 0.510 g (1.57 mmol) of cesium carbonate and 0.043 g (0, 05 mmol) of [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) in 5 mL of a 9/1 mixture of tetrahydrofuran and water.
  • the medium is stirred at 65 ° C. for 4 hours.
  • the medium is then diluted with 50 ml of dichloromethane and 50 ml of water.
  • the biphasic medium is then filtered on a hydrophobic cartridge (liquid / liquid extraction column 70 ml, Radleys®).
  • the organic phase is recovered and concentrated under reduced pressure after adding 1.5 g of silica.
  • the residue obtained is chromatographed on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1/1).
  • the compounds according to the invention have been the subject of pharmacological tests for determining their modulatory effect on NOT.
  • the activity of the compounds according to the invention was evaluated on a cell line (N2A) endogenously expressing the Nurr1 mouse receptor and stably transfected with the NOT binding response element (NBRE) coupled to the luciferase reporter gene. The tests were carried out according to the procedure described below.
  • the Neuro-2A cell line comes from a standard commercial source (ATCC).
  • the Neuro-2A clone was obtained from a spontaneous tumor from an albino mouse A strain by RJ Klebe et al. This Neuro-2A line is then stably transfected with 8NBRE-luciferase.
  • the N2A-8NBRE cells are cultured to confluence in 75 cm 2 culture flasks containing DMEM supplemented with 10% fetal calf serum, 4.5 g / l glucose and 0.4 mg / ml Geneticin. .
  • the cells are recovered with 0.25% trypsin for 30 seconds and then resuspended in DMEM without phenol red containing 4.5 g / l of glucose, 10% of delipidated serum Hyclone and deposited in 96-well white plates with transparent bottom.
  • the cells are deposited at a rate of 60,000 per well in 75 ⁇ L for 24 hours before the addition of the products.
  • the products are applied in 25 ⁇ l and incubated for a further 24 hours.
  • an equivalent volume (100 ⁇ L) of Steadylite is added to each well, then waited for 30 minutes to obtain a complete lysis of the cells and the maximum production of the signal.
  • the plates are then measured in a microplate luminescence counter after being sealed with an adhesive film.
  • the products are prepared as a stock solution at 10 -2 M, then diluted in 100% DMSO. Each product concentration is previously diluted in culture medium before incubation with the cells thus containing 0.625% final DMSO.
  • the best compounds have an EC50 of between 0.1 nM and 10 ⁇ M.
  • Compounds Nos. 2, 4, 10, 14, 16 and 26 showed an EC50 of 45; 2; 6.6; 125; 326 and 1.3 nM respectively.
  • the compounds according to the invention can therefore be used for the preparation of medicaments for their therapeutic application in the treatment or prevention of diseases involving NOT receptors.
  • the subject of the invention is medicaments which comprise a compound of formula (I), or an acid addition salt thereof. pharmaceutically acceptable.
  • Neurodegenerative diseases such as Parkinson's disease, Alzheimer's, tauopathies (eg, supranuclear progressive paralysis, fronto-temporal dementia, corticobasal degeneration).
  • Pick's disease brain trauma such as ischemia and head trauma and epilepsy; psychiatric illnesses such as schizophrenia, depression, substance dependence, attention deficit disorder and hyperactivity disorder; inflammatory diseases of the central nervous system such as multiple sclerosis, encephalitis, myelitis and encephalomyelitis and other inflammatory diseases such as vascular diseases, atherosclerosis, inflammation of the joints, osteoarthritis, rheumatoid arthritis; osteoarthritis, Crohn's disease, ulcerative colitis; allergic inflammatory diseases such as asthma, autoimmune diseases such as type 1 diabetes, lupus, scleroderma, Guillain-Barré syndrome, Addison's disease and other immuno-mediated diseases; osteoporosis; cancers.
  • These compounds could also be used as a treatment associated with stem cell transplants and / or transplants.
  • the present invention relates to pharmaceutical compositions comprising, as active principle, a compound according to the invention.
  • These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt, of said compound, as well as at least one pharmaceutically acceptable excipient.
  • Said excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art.
  • compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration the active ingredient of formula (I) above, or its salt, may be administered in unit dosage form, in admixture with conventional pharmaceutical excipients, to animals and humans for the prophylaxis or treatment of the above disorders or diseases.
  • Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal forms of administration. by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, administration forms rectal and implants.
  • the compounds according to the invention can be used in creams, gels, ointments or lotions.
  • a unitary form of administration of a compound according to the invention in tablet form may comprise the following components: Compound according to the invention 50.0 mg mannitol 223.75 mg Croscarmellose sodium 6.0 mg Corn starch 15.0 mg Hydroxypropylmethylcellulose 2.25 mg Magnesium stearate 3.0 mg
  • the dosage appropriate to each patient is determined by the physician according to the mode of administration, the weight and the response of said patient.
  • the present invention also discloses a method of treating the above-indicated pathologies which comprises administering to a patient an effective dose of a compound of the invention, or a pharmaceutically acceptable salt thereof.

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Description

La présente invention se rapporte à des dérivés de diphényl-pyrazolopyridines, à leur préparation et à leur application en thérapeutique dans le traitement ou la prévention de maladies impliquant les récepteurs nucléaires Nurr-1, aussi appelés NR4A2, NOT, TTNUR, RNR-1, et HZF3.The present invention relates to diphenyl-pyrazolopyridine derivatives, to their preparation and to their therapeutic application in the treatment or prevention of diseases involving the nuclear Nurr-1 receptors, also called NR4A2, NOT, TTNUR, RNR-1, and HZF3.

Des composés mis en oeuvre en thérapeutique dans le traitement ou la prévention de telles maladies sont déjà connus dans l'art antérieur, notamment dans W02008/034974 et FR2928921 . Toutefois, les composés selon la présente invention se distinguent des composés de ces documents en ce qu'ils consistent en des 2,5-diphényl-pyrazolo[1,5-a]pyridines, tandis que les composés de ces documents consistent en des 2,6-diphényl-imidazo[1,2-a]pyridines.Compounds used therapeutically in the treatment or prevention of such diseases are already known in the prior art, particularly in W02008 / 034974 and FR2928921 . However, the compounds according to the present invention are distinguished from the compounds of these documents in that they consist of 2,5-diphenyl-pyrazolo [1,5- a ] pyridines, whereas the compounds of these documents consist of 6-diphenylimidazo [1,2- a ] pyridines.

La présente invention a pour objet les composés de formule (I) :

Figure imgb0001
dans laquelle :

  • R représente un atome d'hydrogène ou d'halogène ou un groupe (C1-C6)alkyle;
  • X représente un ou plusieurs substituants choisis parmi un atome d'hydrogène ou d'halogène, un groupe (C1-C6)alkyle, halogéno(C1-C6)alkyle, (C1-C6)alcoxy, halogéno (C1 -C6)alcoxy, cyano, hydroxy ou hydroxy(C1-C6)alkyle;
  • Y représente un atome d'hydrogène, d'halogène ou un groupe (C1-C6)alkyle;
  • R1 représente un groupe NR2R3 ou OR4;
  • R2 et R3 représentant indépendamment l'un de l'autre, un atome d'hydrogène, un groupe (C1-C6)alkyle, hydroxy(C1-C6)alkyle ou oxo(C1-C6)alkyle, ou bien R2 et R3 forment avec l'atome d'azote qui les porte un hétérocycle éventuellement substitué par un groupe(C1-C6)alkyle, hydroxy ou oxo,
  • R4 représente un groupe (C1-C6)alkyle, hydroxy(C1-C6)alkyle ou oxo(C1-C6)alkyle, à l'état de base ou de sol d'addition à un acide.
The subject of the present invention is the compounds of formula (I):
Figure imgb0001
 in which :
  • R represents a hydrogen or halogen atom or a (C 1 -C 6) alkyl group;
  • X represents one or more substituents chosen from a hydrogen or halogen atom, a (C1-C6) alkyl, halogen (C1-C6) alkyl, (C1-C6) alkoxy, halogen (C1-C6) alkoxy group, cyano, hydroxy or hydroxy (C1-C6) alkyl;
  • Y represents a hydrogen atom, halogen atom or a (C1-C6) alkyl group;
  • R1 is NR2R3 or OR4;
  • R2 and R3 represent, independently of one another, a hydrogen atom, a (C1-C6) alkyl, hydroxy (C1-C6) alkyl or oxo (C1-C6) alkyl group, or R2 and R3 form with the nitrogen atom carrying them a heterocycle optionally substituted by a (C 1 -C 6) alkyl, hydroxy or oxo group,
  • R4 represents a (C1-C6) alkyl, hydroxy (C1-C6) alkyl or oxo (C1-C6) alkyl group, in the form of a base or an acid addition sol.

Les composés de formule (I) peuvent comporter un ou plusieurs atomes de carbone asymétriques. Ils peuvent donc exister sous forme d'énantiomères ou de diastéréoisomères. Ces Enantiomères, diastéréoisoméres, ainsi que leurs mélanges, y compris les mélanges racémiques, font partie de l'invention.The compounds of formula (I) may comprise one or more asymmetric carbon atoms. They can therefore exist as enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including racemic mixtures, form part of the invention.

Les composés de formule (I) peuvent exister à l'état de bases ou de sels d'addition à des acides. De tels sels d'addition font partie de l'invention.The compounds of formula (I) may exist in the form of bases or addition salts with acids. Such addition salts are part of the invention.

Ces sels peuvent être préparés avec des acides pharmaceutiquement acceptables, mais les sels d'autres acides utiles, par exemple, pour la purification ou l'isolement des composés de formule (I) font également partie de l'invention.These salts can be prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for the purification or the isolation of the compounds of formula (I) are also part of the invention.

Les composés de formule (I) peuvent également exister sous forme d'hydrates ou de solvates, à savoir sous forme d'associations ou de combinaisons avec une ou plusieurs molécules d'eau ou avec un solvant. De tels hydrates et solvates font également partie de l'invention.The compounds of formula (I) may also exist in the form of hydrates or solvates, namely in the form of associations or combinations with one or more molecules of water or with a solvent. Such hydrates and solvates are also part of the invention.

Dans le cadre de la présente invention, on entend par :

  • un groupe (Cx-Ct) : un groupe comprenant entre x et t atomes de carbone ;
  • un atome d'halogène : un fluor, un chlore, un brome ou un iode ;
  • un groupe alkyle : un groupe aliphatique saturé linéaire, ramifié ou cyclique, éventuellement substitué par un groupe alkyle saturé linéaire, ramifié ou cyclique. A titre d'exemples, on peut citer les groupes méthyle, éthyle, propyle, isopropyle, butyle, isobutyle, tertbutyle, cyclopropyle, cyclobutyl, cyclopentyle, cyclohexyle, méthylcyclopropyle, cyclopropylméthyle etc ;
  • un groupe alcoxy : un radical -O-alkyle où le groupe alkyle est tel que précédemment défini ;
  • un groupe haloalkyle : un groupe alkyle substitué par un ou plusieurs atomes d'halogène identiques ou différents. A titre d'exemples, on peut citer les groupes CF3, CH2CF3,
In the context of the present invention, the following terms mean:
  • a group (C x -C t ): a group comprising between x and t carbon atoms;
  • a halogen atom: a fluorine, a chlorine, a bromine or an iodine;
  • an alkyl group: a linear, branched or cyclic saturated aliphatic group optionally substituted by a linear, branched or cyclic saturated alkyl group. By way of examples, mention may be made of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl or cyclopropylmethyl groups;
  • an alkoxy group: an -O-alkyl radical where the alkyl group is as previously defined;
  • a haloalkyl group: an alkyl group substituted with one or more identical or different halogen atoms. By way of examples, mention may be made of the groups CF 3 , CH 2 CF 3 ,

CHF2, CCl3.

  • un groupe hydroxyalkyle : un groupe alkyle substitué par un groupe hydroxyle; à titre d'exemples, on peut citer CH2OH, CH2CH2OH etc.
  • un groupe oxoalkyle : un groupe alkyle substitué par un groupe oxo (C=O); à titre d'exemples, on peut citer CH3CO, CH3COCH2 etc.
  • un groupe haloalcoxy : un radical -O-alkyle où le groupe alkyle est tel que précédemment défini et substitué par un ou plusieurs atomes d'halogène identiques ou différents. A titre d'exemples, on peut citer les groupes OCF3, OCHF2, OCCl3
  • un groupe aryle : groupe mono ou bicyclique aromatique comportant de 6 à 10 atomes.
CHF 2 , CCl 3 .
  • a hydroxyalkyl group: an alkyl group substituted with a hydroxyl group; by way of examples, mention may be made of CH 2 OH, CH 2 CH 2 OH, and the like.
  • an oxoalkyl group: an alkyl group substituted with an oxo group (C = O); as examples, there may be mentioned CH3CO, CH3COCH2 etc.
  • a haloalkoxy group: an -O-alkyl radical where the alkyl group is as previously defined and substituted by one or more identical or different halogen atoms. By way of examples, mention may be made of groups OCF 3 , OCHF 2 and OCCl 3
  • an aryl group: mono- or bicyclic aromatic group containing from 6 to 10 atoms.

A titre d'exemples de groupes aryles, on peut citer phényle et naphthyle.

  • un groupe hétérocycle : un groupe cyclique saturé, azoté, éventuellement ponté, comprenant entre 5 et 9 atomes de carbone, au moins un atome d'azote et comprenant éventuellement entre 1 et 3 hétéroatomes additionnels, tels que l'oxygène, l'azote ou le soufre. On peut notamment citer les groupes pipéridinyle, pipérazinyle, pyrrolidinyle, morpholinyle etc.
As examples of aryl groups, mention may be made of phenyl and naphthyl.
  • a heterocycle group: a saturated, nitrogen-containing, optionally bridged cyclic group comprising between 5 and 9 carbon atoms, at least one nitrogen atom and optionally comprising between 1 and 3 additional heteroatoms, such as oxygen, nitrogen or sulfur. In particular, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl and the like may be mentioned.

Parmi les composés de formule (I) objets de l'invention, un premier groupe de composés est constitué des composés pour lesquels :

  • R représente un atome d'hydrogène ou de chlore,
  • X représente un ou plusieurs substituants choisis parmi un atome d'halogène, un groupe (C1 - C6)alkyle, halogéno(C1-C6)alkyle, (C1-C6)alcoxy, halogéno(C1-C6)alcoxy, ou cyano,
  • Y représente un atome d'hydrogène, un atome d'halogène ou un groupe (C1-C6)alkyle;
  • R1 représente un groupe OR4,
  • R4 représente un groupe méthyle, à l'état de base ou de sel d'addition à un acide.
Among the compounds of formula (I) which are subjects of the invention, a first group of compounds consists of compounds for which:
  • R represents a hydrogen or chlorine atom,
  • X represents one or more substituents selected from a halogen atom, a (C1-C6) alkyl, halogen (C1-C6) alkyl, (C1-C6) alkoxy, halogen (C1-C6) alkoxy, or cyano,
  • Y represents a hydrogen atom, a halogen atom or a (C1-C6) alkyl group;
  • R1 represents a group OR4,
  • R4 represents a methyl group, in the form of a base or an addition salt with an acid.

Parmi les composés de formule (I) objets de l'invention, un second groupe de composés est constitué des composés pour lesquels :

  • R représente un atome d'hydrogène ou de chlore,
  • X représente un ou plusieurs substituants choisis parmi un atome de chlore ou de fluor, un groupe méthyle, trifluorométhyle, méthoxy, trifluorométhoxy ou cyano,
  • Y représente un atome d'hydrogène, de chlore, de fluor ou un groupe méthyle;
  • R1 représente un groupe OR4,
  • R4 représente un groupe méthyle, à l'état de base ou de sel d'addition à un acide.
Among the compounds of formula (I) that are subjects of the invention, a second group of compounds consists of compounds for which:
  • R represents a hydrogen or chlorine atom,
  • X represents one or more substituents chosen from a chlorine or fluorine atom, a methyl, trifluoromethyl, methoxy, trifluoromethoxy or cyano group,
  • Y represents a hydrogen, chlorine, fluorine atom or a methyl group;
  • R1 represents a group OR4,
  • R4 represents a methyl group, in the form of a base or an addition salt with an acid.

Parmi les composés de formule (I) objets de l'invention, un troisième groupe de composés est constitué des composés pour lesquels :

  • R représente un atome d'hydrogène ou de chlore ;
  • X représente un ou plusieurs substituants choisis parmi un un atome d'halogène, un groupe (C1-C6)alkyle, halogéno(C1-C6)alkyle, (C1-C6)alcoxy, halogéno(C1-C6)alcoxy, ou cyano ;
  • Y représente un atome d'hydrogène, un atome d'halogène ou un groupe (C1-C6)alkyle;
  • R1 représente un groupe NR2R3,
  • R2 et R3 représentent, indépendamment l'un de l'autre, un atome d'hydrogène, un groupe méthyle, éthyle, isopropyle, cyclopropyle, ou bien R2 et R3 forment avec l'atome d'azote qui les porte un groupe morpholinyle ou pyrrolidine éventuellement substitué par un groupe hydroxy, à l'état de base ou de sel d'addition à un acide.
Among the compounds of formula (I) which are subjects of the invention, a third group of compounds consists of compounds for which:
  • R represents a hydrogen or chlorine atom;
  • X represents one or more substituents selected from a halogen atom, a (C1-C6) alkyl, halo (C1-C6) alkyl, (C1-C6) alkoxy, halo (C1-C6) alkoxy, or cyano group;
  • Y represents a hydrogen atom, a halogen atom or a (C1-C6) alkyl group;
  • R1 represents a group NR2R3,
  • R2 and R3 represent, independently of one another, a hydrogen atom, a methyl, ethyl, isopropyl or cyclopropyl group, or else R2 and R3 form with the nitrogen atom which carries them a morpholinyl group or pyrrolidine optionally substituted with a hydroxy group, in the form of a base or an addition salt with an acid.

Parmi les composés de formule (I) objets de l'invention, un quatrième groupe de composés est constitué des composés pour lesquels :

  • R représente un atome d'hydrogène ou de chlore,
  • X représente un ou plusieurs substituants choisis parmi un atome de chlore ou de fluor, un groupe méthyle, trifluorométhyle, méthoxy, trifluorométhoxy ou cyano,
  • Y représente un atome d'hydrogène ou de chlore ou un groupe méthyle ;
  • R1 représente un groupe NR2R3,
  • R2 et R3 représentent, indépendamment l'un de l'autre, un atome d'hydrogène, un groupe méthyle, éthyle, isopropyle, cyclopropyle, ou bien R2 et R3 forment avec l'atome d'azote qui les porte un groupe morpholinyle ou pyrrolidine éventuellement substitué par un groupe hydroxy, à l'état de base ou de sel d'addition à un acide.
Among the compounds of formula (I) that are the subject of the invention, a fourth group of compounds consists of compounds for which:
  • R represents a hydrogen or chlorine atom,
  • X represents one or more substituents selected from a chlorine or fluorine atom, a methyl, trifluoromethyl, methoxy, trifluoromethoxy or cyano group,
  • Y represents a hydrogen or chlorine atom or a methyl group;
  • R1 represents a group NR2R3,
  • R2 and R3 represent, independently of one another, a hydrogen atom, a methyl, ethyl, isopropyl or cyclopropyl group, or else R2 and R3 form with the nitrogen atom which carries them a morpholinyl group or pyrrolidine optionally substituted with a hydroxy group, in the form of a base or an addition salt with an acid.

Les combinaisons des groupes un à quatre tels que définis ci dessus font également partie de l'invention.The combinations of groups one to four as defined above are also part of the invention.

Parmi les composés de formule (I) objets de l'invention, on peut notamment citer les composés suivants :

  • 3-[2-(4-Chlororophényl)pyrazolo[1,5-a]pyridin-5-yl]benzoate de méthyle
  • 3-[2-(4-Chlorophényl)pyrazolo[1,5-a]pyridin-5-yl]benzamide
  • 3-[2-(4-Chlorophényl)pyrazolo[1,5-a]pyridin-5-yl]-N,N-diméthylbenzamide
  • 3-[2-(4-Chlorophényl)pyrazolo[1,5-a]pyridin-5-yl]-N-méthylbenzamide
  • 3-[2-(4-Fluorophényl)pyrazolo[1,5-a]pyridin-5-yl]benzoate de méthyle
  • 3-[2-(4-Fluorophényl)pyrazolo[1,5-a]pyridin-5-yl]-N-méthylbenzamide
  • 3-[2-(4-Fluorophényl)pyrazolo[1,5-a]pyridin-5-yl]-N-isopropylbenzamide
  • 3-[2-(4-Fluorophényl)pyrazolo[1,5-a]pyridin-5-yl]-N,N-diméthylbenzamide
  • {3-[2-(4-Fluorophényl)pyrazolo[1,5-a]pyridin-5-yl]phényl}morpholin-4-yl-méthanone
  • 3-[2-(4-Fluorophényl)pyrazolo[1,5-a]pyridin-5-yl]-2,N-diméthylbenzamide
  • 2-Chloro-5-[2-(4-fluorophényl)pyrazolo[1,5-a]pyridin-5-yl]-N-méthylbenzamide
  • 4-Chloro-3-[2-(4-fluorophényl)pyrazolo[1,5-a]pyridin-5-yl]-N-méthylbenzamide
  • 3-[2-(4-Fluorophényl)pyrazolo[1,5-a]pyridin-5-yl]-4,N-diméthylbenzamide
  • 2-Fluoro-4-[2-(4-fluorophényl)pyrazolo[1,5-a]pyridin-5-yl]-N-méthylbenzamide
  • N-Cyclopropyl-3-[2-(4-fluorophényl)pyrazolo[1,5-a]pyridin-5-yl]benzamide
  • {3-[2-(4-Fluorophényl)pyrazolo[1,5-a]pyridin-5-yl]phényl}pyrrolidin-1-ylméthanone
  • 3-[2-(2,6-Difluorophényl)pyrazolo[1,5-a]pyridin-5-yl-méthylbenzamide
  • 3-[2-(2-Fluorophényl)pyrazolo[1,5-a]pyridin-5-yl]-N-méthylbenzamide
  • N-Méthyl-3-[2-(4-trifluorométhylphényl)pyrazolo[1,5-a]pyridin-5-yl]benzamide
  • 4-[2-(4-Fluorophényl)pyrazolo[1,5-a]pyridin-5-yl]-N-méthylbenzamide
  • 2-[2-(4-Fluorophényl)pyrazolo[1,5-a]pyridin-5-yl]-N-méthylbenzamide
  • {3-[2-(4-Fluorophényl)pyrazolo[1,5-a]pyridin-5-yl]phényl}-(3-hydroxypyrrolidin-1-yl)méthanone
  • 3-[2-(2,4-Difluorophényl)pyrazolo[1,5-a]pyridin-5-yl]-N-méthylbenzamide
  • N-Méthyl-3-[2-(4-trifluorométhoxyphényl)pyrazolo[1,5-a]pyridin-5-yl]benzamide
  • 3-[2-(3,4-Difluorophényl)pyrazolo[1,5-a]pyridin-5-yl]-N-méthylbenzamide
  • 3-[2-(3,5-Difluorophényl)pyrazolo[1,5-a]pyridin-5-yl]-N-méthylbenzamide
  • 3-[2-(3-Fluorophényl)pyrazolo[1,5-a]pyridin-5-yl]-N-méthylbenzamide
  • N-Méthyl-3-(2-p-tolylpyrazolo[1,5-a]pyridin-5-yl)benzamide
  • 3-[2-(4-Méthoxyphényl)pyrazolo[1,5-a]pyridin-5-yl]-N-méthylbenzamide
  • 3-[2-(3,4-Diméthylphényl)pyrazolo[1,5-a]pyridin-5-yl]-N-méthylbenzamide
  • 3-[2-(4-Cyanophényl)pyrazolo[1,5-a]pyridin-5-yl]-N-méthylbenzamide
  • 3-[2-(2,3-Difluorophényl)pyrazolo[1,5-a]pyridin-5-yl]-N-méthylbenzamide
  • N-Méthyl-3-(2-o-tolylpyrazolo[1,5-a]pyridin-5-yl)benzamide
  • 3-[3-Chloro-2-(4-fluorophényl)pyrazolo[1,5-a]pyridin-5-yl]-N-méthylbenzamide
Among the compounds of formula (I) that are subjects of the invention, mention may be made especially of the following compounds:
  • Methyl 3- [2- (4-chlorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] benzoate
  • 3- [2- (4-Chlorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] benzamide
  • 3- [2- (4-Chlorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] -N , N- dimethylbenzamide
  • 3- [2- (4-Chlorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] -N- methylbenzamide
  • Methyl 3- [2- (4-Fluorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] benzoate
  • 3- [2- (4-Fluorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] -N- methylbenzamide
  • 3- [2- (4-Fluorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] -N- isopropylbenzamide
  • 3- [2- (4-Fluorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] -N , N- dimethylbenzamide
  • {3- [2- (4-Fluorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] phenyl} morpholin-4-yl-methanone
  • 3- [2- (4-Fluorophenyl) pyrazolo [1,5-a] pyridin-5-yl] -2, N -diméthylbenzamide
  • 2-Chloro-5- [2- (4-fluorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] -N- methylbenzamide
  • 4-Chloro-3- [2- (4-fluorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] -N- methylbenzamide
  • 3- [2- (4-Fluorophenyl) pyrazolo [1,5-a] pyridin-5-yl] -4, N -diméthylbenzamide
  • 2-Fluoro-4- [2- (4-fluorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] -N- methylbenzamide
  • N- Cyclopropyl-3- [2- (4-fluorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] benzamide
  • {3- [2- (4-Fluorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] phenyl} pyrrolidin-1-ylmethanone
  • 3- [2- (2,6-Difluorophenyl) pyrazolo [1,5- a ] pyridin-5-yl-methylbenzamide
  • 3- [2- (2-Fluorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] -N- methylbenzamide
  • N- methyl-3- [2- (4-trifluoromethylphenyl) pyrazolo [1,5- a ] pyridin-5-yl] benzamide
  • 4- [2- (4-Fluorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] -N- methylbenzamide
  • 2- [2- (4-Fluorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] -N- methylbenzamide
  • {3- [2- (4-Fluorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] phenyl} - (3-hydroxypyrrolidin-1-yl) methanone
  • 3- [2- (2,4-Difluorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] -N- methylbenzamide
  • N- methyl-3- [2- (4-trifluoromethoxyphenyl) pyrazolo [1,5- a ] pyridin-5-yl] benzamide
  • 3- [2- (3,4-Difluorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] -N- methylbenzamide
  • 3- [2- (3,5-Difluorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] -N- methylbenzamide
  • 3- [2- (3-Fluorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] -N- methylbenzamide
  • N- methyl-3- (2-p-tolylpyrazolo [1,5- a ] pyridin-5-yl) benzamide
  • 3- [2- (4-Methoxyphenyl) pyrazolo [1,5- a ] pyridin-5-yl] -N- methylbenzamide
  • 3- [2- (3,4-Dimethylphenyl) pyrazolo [1,5- a ] pyridin-5-yl] -N- methylbenzamide
  • 3- [2- (4-Cyanophenyl) pyrazolo [1,5- a ] pyridin-5-yl] -N- methylbenzamide
  • 3- [2- (2,3-Difluorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] -N- methylbenzamide
  • N-Methyl-3- (2-o-tolylpyrazolo [1,5- a ] pyridin-5-yl) benzamide
  • 3- [3-Chloro-2- (4-fluorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] -N- methylbenzamide

Conformément à l'invention, on peut préparer les composés de formule générale (I) selon le procédé décrit dans le schéma 1.

Figure imgb0002
According to the invention, the compounds of general formula (I) can be prepared according to the process described in scheme 1.
Figure imgb0002

Suivant le schéma 1, on peut préparer les composés de formule générale (Ia), dans laquelle R1 représente OR4, R4 représente un groupe alkyle ALK, R représente un atome d'hydrogène, X et Y sont définis comme précédemment, par une réaction de couplage, catalysée par un métal tel que le palladium, entre un composé de formule générale (II) dans laquelle R représente un atome d'hydrogène, X est défini tel que précédemment et Hal représente un atome d'halogène, et un dérivé de formule générale (III) dans laquelle Y et ALK sont définis tel que précédemment, et Z représente un dérivé de bore.According to Scheme 1, the compounds of the general formula (Ia), in which R 1 represents OR 4, R 4 represents an alkyl group ALK, R represents a hydrogen atom, X and Y are defined as above, can be prepared by a reaction of metal-catalyzed coupling, such as palladium, between a compound of general formula (II) in which R represents a hydrogen atom, X is defined as above and Hal represents a halogen atom, and a derivative of formula general (III) wherein Y and ALK are defined as above, and Z represents a boron derivative.

Suivant le schéma 1, on peut préparer les composés de formule générale (Ib), dans laquelle R1 représente OR4, R représente un atome d'hydrogène, X et Y sont définis comme précédemment et R4 représente un atome d'hydrogène, par une réaction d'hydrolyse des composés de formule générale (Ia) par une base telle que la soude dans un milieu hydro-alcoolique.According to Scheme 1, the compounds of general formula (Ib), in which R 1 represents OR 4, R represents a hydrogen atom, X and Y are defined as above and R 4 represents a hydrogen atom, by a reaction hydrolysis of compounds of general formula (Ia) with a base such as sodium hydroxide in a hydro-alcoholic medium.

Suivant le schéma 1 voie A , on peut préparer les composés de formule générale (Ic) dans laquelle R1 représente NR2R3, R représente un atome d'hydrogène et X, Y, R2 et R3 sont définis comme précédemment, par une réaction de couplage, catalysée par un métal tel que le palladium, entre un composé de formule générale (II) dans laquelle R représente un atome d'hydrogène, X est défini tel que précédemment et Hal représente un atome d'halogène et un dérivé de formule générale (IV) dans laquelle Y, R2 et R3 sont définis tel que précédemment et Z représente un dérivé de bore.According to Scheme 1, route A , the compounds of general formula (Ic) in which R 1 represents NR 2 R 3, R represents a hydrogen atom and X, Y, R 2 and R 3 are defined as above, by a coupling reaction, catalyzed by a metal such as palladium, between a compound of general formula (II) in which R represents a hydrogen atom, X is defined as above and Hal represents an atom of halogen and a derivative of general formula (IV) wherein Y, R2 and R3 are defined as above and Z represents a boron derivative.

Suivant le schéma 1 voie B , on peut préparer les composés de formule générale (Ic) dans laquelle R1 représente NR2R3, R représente un atome d'hydrogène et X, Y, R2 et R3 sont définis comme précédemment, par une réaction entre un composé de formule générale (Ia), dans laquelle R1 représente OR4, R4 représente un groupe alkyle ALK, R représente un atome d'hydrogène, X, Y sont définis comme précédemment, et une amine de formule générale (V) dans laquelle R2 et R3 sont définis comme précédemment, en présence de triméthylaluminium en solution ou bien complexé avec une amine tertiaire telle que le DABCO selon la méthode décrite par D. Glynn, D. Bernier, S. Woodward dans Tetrahedron Letters, 2008, 49, 5687-5688 .According to Scheme 1, route B , the compounds of general formula (Ic) in which R 1 represents NR 2 R 3, R represents a hydrogen atom and X, Y, R 2 and R 3 are defined as above, can be prepared by a reaction between a compound of general formula (Ia), wherein R1 represents OR4, R4 represents an alkyl group ALK, R represents a hydrogen atom, X, Y are defined as above, and an amine of general formula (V) in which R2 and R3 are defined as above, in the presence of trimethylaluminum in solution or complexed with a tertiary amine such as DABCO according to the method described by D. Glynn, D. Bernier, S. Woodward in Tetrahedron Letters, 2008, 49, 5687-5688 .

Suivant le schéma 1 voie C, on peut préparer les composés de formule générale (Ic) dans laquelle R1 représente NR2R3, R représente un atome d'hydrogène et X, Y, R2 et R3 sont définis comme précédemment par une réaction entre un composé de formule générale (Ib), dans laquelle R1 représente OR4, R représente un atome d'hydrogène, X et Y sont définis comme précédemment et R4 représente un atome d'hydrogène, et une amine de formule générale (V) dans laquelle R2 et R3 sont définis comme précédemment, en présence d'un activateur d'acide tel que le chloroformate d'isobutyle.According to Scheme 1, route C , the compounds of general formula (Ic) in which R 1 represents NR 2 R 3, R represents a hydrogen atom and X, Y, R 2 and R 3 are defined as previously by a reaction between a compound of general formula (Ib), wherein R1 represents OR4, R represents a hydrogen atom, X and Y are defined as above and R4 represents a hydrogen atom, and an amine of general formula (V) in which R2 and R3 are defined as above, in the presence of an acid activator such as isobutyl chloroformate.

Suivant le schéma 1 voie D , on peut préparer les composés de formule générale (le) dans laquelle R1 représente NR2R3, R représente un atome d'hydrogène et X, Y, R2 et R3 sont définis comme précédemment par une réaction de couplage, catalysée par un métal tel que le palladium, entre un composé de formule générale (VI) dans laquelle R représente un atome d'hydrogène, X est défini tel que précédemment et Z représente un dérivé de bore et un dérivé de formule générale (VII) dans laquelle Y, R2 et R3 sont définis tel que précédemment et Hal. représente un atome d'halogène.According to Scheme 1, route D , the compounds of general formula (Ic) in which R 1 represents NR 2 R 3, R represents a hydrogen atom and X, Y, R 2 and R 3 are defined as above by a catalyzed coupling reaction can be prepared. by a metal such as palladium, between a compound of general formula (VI) in which R represents a hydrogen atom, X is defined as above and Z represents a boron derivative and a derivative of general formula (VII) in which Y, R2 and R3 are defined as above and Hal. represents a halogen atom.

On peut également préparer les composés de formule générale (Ic) dans laquelle R2 et R3 représentent chacun un atome d'hydrogène selon le procédé décrit dans le schéma 2.

Figure imgb0003
Figure imgb0004
 The compounds of general formula (Ic) in which R2 and R3 each represent a hydrogen atom can also be prepared according to the process described in scheme 2.
Figure imgb0003
Figure imgb0004

Dans le schéma 2, les composés de formule générale (Ic) dans laquelle R1 représente NH2, R représente un atome d'hydrogène et X et Y sont définis comme précédemment, peuvent être obtenus par hydrolyse des nitriles de formule générale (IX), par exemple au moyen d'eau oxygénée en présence de base. Les composés de formule générale (IX) peuvent être obtenus par une réaction de couplage, catalysée par un métal tel que le palladium, entre un composé de formule générale (II) dans laquelle R représente un atome d'hydrogène, X est défini tel que précédemment et Hal représente un atome d'halogène et un dérivé de formule générale (VIII) dans laquelle Y est défini tel que précédemment, CN représente un groupe cyano et Z représente un dérivé de bore.In Scheme 2, the compounds of general formula (Ic) in which R 1 represents NH 2, R represents a hydrogen atom and X and Y are defined as above, can be obtained by hydrolysis of the nitriles of general formula (IX), by example using oxygenated water in the presence of base. The compounds of general formula (IX) can be obtained by a metal-catalyzed coupling reaction such as palladium between a compound of general formula (II) in which R represents a hydrogen atom, X is defined such that previously and Hal represents a halogen atom and a derivative of general formula (VIII) wherein Y is defined as above, CN represents a cyano group and Z represents a boron derivative.

Conformément à l'invention, on peut préparer les composés de formule générale (I) selon le procédé décrit dans le schéma 3.

Figure imgb0005
According to the invention, the compounds of general formula (I) can be prepared according to the process described in scheme 3.
Figure imgb0005

Suivant le schéma 3, on peut préparer les composés de formule générale (Id) dans laquelle X, Y et R1 sont définis comme précédemment et R représente un atome d'halogène Hal par halogénation électrophile des composés (Ia) ou (Ic), par exemple par chloration, au moyen d'un agent tel que la N-chlorosuccinimide.According to Scheme 3, the compounds of general formula (Id) in which X, Y and R 1 are defined as above and R represents a Hal halogen atom by electrophilic halogenation of compounds (Ia) or (Ic), can be prepared by example by chlorination, using an agent such as N- chlorosuccinimide.

Conformément à l'invention, on peut préparer les composés de formule générale (II) et (VI) selon le procédé décrit dans le schéma 4.

Figure imgb0006
According to the invention, the compounds of general formula (II) and (VI) can be prepared according to the process described in scheme 4.
Figure imgb0006

Dans le schéma 4 voie A, les composés de formule générale (II) dans laquelle X est défini comme précédemment, R représente un atome d'hydrogène et Hal représente un atome d'halogène peuvent être préparés par action du O-(mésitylènesulfonyl)hydroxylamine (MSH) sur un composé de formule générale (XIII) dans laquelle X et Hal sont définis comme précédemment, par exemple selon la méthode décrite par Y. Tamura, J.-H. Kim, Y. Miki, H. Hayashi, M. Ikeda, dans J.Het. Chem., 1975, 12, 481 .In the 4- way A scheme , the compounds of general formula (II) wherein X is defined as above, R represents a hydrogen atom and Hal represents a halogen atom can be prepared by the action of O- (mesitylenesulfonyl) hydroxylamine (MSH) on a compound of general formula (XIII) in which X and Hal are defined as above, for example according to the method described by Y. Tamura, J.-H. Kim, Y. Miki, H. Hayashi, M. Ikeda, in J.Het. Chem., 1975, 12, 481 .

Dans le schéma 4 voie B , on peut également préparer les composés de formule générale (II) dans laquelle X est défini comme précédemment, R représente un atome d'hydrogène et Hal représente un atome d'halogène par transformation des composés de formule générale (XIII) en composés de formule générale (XIV) dans laquelle X et Hal sont définis comme précédemment, par action d'un anhydride d'acide tel que l'anhydride trifluoracétique en présence d'une base telle que la triéthylamine, puis cyclisation en composés de formule générale (II) en présence d'un catalyseur comme le chlorure ferreux, par exemple selon la méthode décrite par K.S. Gudmundsson dans Bioorg. Med. Chem., 2005, 13, 5346 .In Scheme 4, route B , the compounds of general formula (II) in which X is defined as above, R represents a hydrogen atom and Hal represents a halogen atom by conversion of the compounds of general formula ( XIII) in compounds of general formula (XIV) in which X and Hal are defined as above, by the action of an acid anhydride such as trifluoroacetic anhydride in the presence of a base such as triethylamine, and then cyclization to compounds of general formula (II) in the presence of a catalyst such as ferrous chloride, for example according to the method described by KS Gudmundsson in Bioorg. Med. Chem., 2005, 13, 5346 .

Les composés (XIII) peuvent être obtenus à partir des composés (XII) par action de l'hydroxylamine. Les composés (XII) peuvent être obtenus à partir des picolines de formule générale (X) et des esters de formule générale (XI) dans laquelle X est défini comme précédemment et ALK représente un groupement alkyle, en présence d'une base forte, par exemple selon la méthode décrite par K.S. Gudmundsson dans Bioorg. Med Chem., 2005, 13, 5346 .Compounds (XIII) can be obtained from compounds (XII) by the action of hydroxylamine. The compounds (XII) can be obtained from picolines of general formula (X) and esters of general formula (XI) in which X is defined as above and ALK represents an alkyl group, in the presence of a strong base, by example according to the method described by KS Gudmundsson in Bioorg. Med Chem., 2005, 13, 5346 .

Enfin, on peut préparer les composés (VI) dans lesquels Z représente un dérivé de bore suivant le schéma 3 par une réaction de couplage, par exemple du bis(pinacolato)dibore, sur les composés (II), catalysée par un métal tel que le palladium selon la méthode décrite par E.F. DiMauro, R.Vitullo, J.Org.Chem., 2006, 71(10), 3959 .Finally, the compounds (VI) in which Z represents a boron derivative according to Scheme 3 can be prepared by a coupling reaction, for example of bis (pinacolato) diborone, on the compounds (II), catalyzed by a metal such as palladium according to the method described by EF DiMauro, R.Vitullo, J.Org.Chem., 2006, 71 (10), 3959 .

Dans les schémas 1, 2, 3 et 4, les composés de départ et les réactifs, quand leur mode de préparation n'est pas décrit, sont disponibles dans le commerce ou décrits dans la littérature, ou bien peuvent être préparés selon des méthodes qui y sont décrites ou qui sont connues de l'Homme du métier.In Schemes 1, 2, 3 and 4, the starting compounds and the reagents, when their method of preparation is not described, are commercially available or described in the literature, or may be prepared according to methods which described therein or which are known to those skilled in the art.

L'invention, selon un autre de ses aspects, a également pour objet le composé de formule (VI-1). Ce composé est utile comme intermédiaire de synthèse des composés de formule (I).

Figure imgb0007
The invention, according to another of its aspects, also relates to the compound of formula (VI-1). This compound is useful as an intermediate for the synthesis of the compounds of formula (I).
Figure imgb0007

Les exemples suivants décrivent la préparation de certains composés conformes à l'invention. Ces exemples ne sont pas limitatifs et ne font qu'illustrer la présente invention. Les numéros des composés exemplifiés renvoient à ceux donnés dans le tableau ci-après, qui illustre les structures chimiques et les propriétés physiques de quelques composés selon l'invention.The following examples describe the preparation of certain compounds according to the invention. These examples are not limiting and only illustrate the present invention. The numbers of the compounds exemplified refer to those given in the table below, which illustrates the chemical structures and the physical properties of some compounds according to the invention.

Exemple 1 : 3-[2-(4-Chlororophényl)pyrazolo[1,5-a]pyridin-5-yl]benzoate de méthyle (composé 1 du tableau) Example 1 Methyl 3- [2- (4-chlorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] benzoate (Compound Compound 1) 1.1 2-(4-Bromopyridin-2-yl)-1-(4-chlorophényl)éthanone1.1 2- (4-Bromopyridin-2-yl) -1- (4-chlorophenyl) ethanone

Sous courant d'azote, 5 g (29,07 mmol) de 4-bromo-2-méthylpyridine et 11,27 g (61,04 mmol) de 4-chlorobenzoate d'éthyle sont placés dans un ballon et dissous dans 50 ml de tétrahydrofurane anhydre. On refroidit à 5°C et on ajoute goutte à goutte 70 mL (70 mmol) d'une solution d'hexaméthyldisilazane de lithium (1M dans le tétrahydrofurane). Après addition, le mélange est agité à température ambiante pendant 2h, refroidi à 5°C, puis 100 mL d'eau sont additionnés progressivement. Le milieu est ensuite dilué avec 250 mL d'acétate d'éthyle et 100 mL d'eau. La phase organique est séparée, la phase aqueuse est extraite deux fois avec 100 ml d'acétate d'éthyle. Les phases organiques sont ensuite réunies, séchées sur sulfate de sodium et filtrées. On ajoute ensuite au filtrat 15 g de silice, concentre sous pression réduite. La poudre obtenue est utilisée comme dépôt solide pour une chromatographie sur gel de silice avec pour éluant un mélange de cyclohexane et d'acétate d'éthyle (9/1). 8,4 g (93%) de composé sont obtenus sous forme d'une poudre jaune.
LC-MS: M+H = 310
RMN-1H (DMSO) δ (ppm) : 4,6 (s, 2H) ; 6,4 (s, 1H) ; 7,4 (s, 1H) ; de 7,5 à 7,6 (m, 6H) ; 7,7 (s, 1H) ; 7,9 (d, 2H) ; 8,1 (d,2H) ; 8,3 (d, 1H) ; 8,4 (d, 1H) ; 15,0 (s, 1H) (mélange cétone / énol: 40 / 60).Under a stream of nitrogen, 5 g (29.07 mmol) of 4-bromo-2-methylpyridine and 11.27 g (61.04 mmol) of ethyl 4-chlorobenzoate are placed in a flask and dissolved in 50 ml. anhydrous tetrahydrofuran. It is cooled to 5 ° C. and 70 ml (70 mmol) of a solution of lithium hexamethyldisilazane (1M in tetrahydrofuran) are added dropwise. After addition, the mixture is stirred at room temperature for 2 h, cooled to 5 ° C, then 100 mL of water are added gradually. The medium is then diluted with 250 mL of ethyl acetate and 100 mL of water. The organic phase is separated, the aqueous phase is extracted twice with 100 ml of ethyl acetate. The organic phases are then combined, dried over sodium sulphate and filtered. 15 g of silica are then added to the filtrate, concentrated under reduced pressure. The powder obtained is used as a solid deposit for chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (9/1). 8.4 g (93%) of compound are obtained in the form of a yellow powder.
LC-MS: M + H = 310
1 H NMR (DMSO) δ (ppm): 4.6 (s, 2H); 6.4 (s, 1H); 7.4 (s, 1H); 7.5 to 7.6 (m, 6H); 7.7 (s, 1H); 7.9 (d, 2H); 8.1 (d, 2H); 8.3 (d, 1H); 8.4 (d, 1H); 15.0 (s, 1H) ( ketone / enol mixture : 40/60 ).

1.2 2-(4-Bromopyridin-2-yl)-1-(4-chlorophényl)éthanone oxime1.2 2- (4-Bromopyridin-2-yl) -1- (4-chlorophenyl) ethanone oxime

On place dans un ballon 8,4 g (27,05 mmol) de 2-(4-bromopyridin-2-yl)-1-(4-chlorophényl)éthanone dans 150 mL d'éthanol. On ajoute 22 mL (272,56 mmol) de pyridine et 7,5 g (107,93 mmol) d'hydroxylamine monochlorhydrate Le mélange est ensuite agité pendant 5 heures à température ambiante puis le milieu réactionnel est concentré sous pression réduite jusqu'à obtention d'un solide pâteux jaune que l'on reprend avec 400mL d'acétate d'éthyle et 400 mL d'eau. La phase organique est séparée, la phase aqueuse est extraite trois fois avec 200 mL d'acétate d'éthyle. Les phases organiques sont ensuite réunies, séchées sur sulfate de sodium et filtrées. Le filtrat est concentré sous pression réduite : on obtient 8,1 g (91,9%) de composé sous forme d'une poudre bleue.
LC-MS : M+H = 325
RMN-1H (DMSO) δ (ppm) : 4,3 (s, 2H) ; 7,45 (m, 2H) ; 7,50 (d, 1H) ; 7,55 (s, 1H) ; 7,75 (m, 2H) ; 8,35 (d, 1H) ; 11,65 (s, 1 H).8.4 g (27.05 mmol) of 2- (4-bromopyridin-2-yl) -1- (4-chlorophenyl) ethanone are placed in a flask in 150 ml of ethanol. 22 mL (272.56 mmol) of pyridine and 7.5 g (107.93 mmol) of hydroxylamine monohydrochloride are added. The mixture is then stirred for 5 hours at ambient temperature and the reaction medium is then concentrated under reduced pressure until obtaining a yellow pasty solid which is taken up with 400 ml of ethyl acetate and 400 ml of water. The organic phase is separated, the aqueous phase is extracted three times with 200 mL of ethyl acetate. The organic phases are then combined, dried over sodium sulphate and filtered. The filtrate is concentrated under reduced pressure to give 8.1 g (91.9%) of compound in the form of a blue powder.
LC-MS: M + H = 325
1 H NMR (DMSO) δ (ppm): 4.3 (s, 2H); 7.45 (m, 2H); 7.50 (d, 1H); 7.55 (s, 1H); 7.75 (m, 2H); 8.35 (d, 1H); 11.65 (s, 1H).

1.3. 5-Bromo-2-(4-chlorophényl)pyrazolo[1,5-a]pyridine1.3. 5-Bromo-2- (4-chlorophenyl) pyrazolo [1,5- a ] pyridine

On place dans un ballon 12,9 g (45,21 mmol) de O-(2-mésitylènesulfonyl)acétohydroxamate d'éthyle dans 30 mL de 1,4-dioxane. On refroidit à 0°C et on ajoute 13,5 mL (156,60 mmol) d'acide perchlorique (70% dans l'eau). On ajoute ensuite 10 mL de 1,4-dioxane puis le milieu est agité vigoureusement pendant 2h30 minutes à 0°C. Le milieu est ensuite versé dans 350mL d'eau glacée. On laisse le milieu vers 0°C pendant 10 minutes puis on récupère par filtration sur verre fritté le solide blanc formé (ne pas sécher totalement, le produit est potentiellement explosif à l'état sec). Le solide pâteux blanc obtenu est lavé avec 350 mL d'eau glacée puis est repris avec 250mL de 1,2-dichloroéthane et 150mL de saumure refroidie vers 5°C. On récupère la phase organique que l'on filtre sur cartouche hydrophobe. On récupère le filtrat que l'on ajoute goutte à goutte sur une solution refroidie vers 0°C de 8,1g (24,88 mmol) de 2-(4-bromopyridin-2-yl)-1-(4-chlorophényl)éthanone oxime (composé obtenu dans l'étape 1.2) dans 150mL de 1,2-dichloroéthane.12.9 g (45.21 mmol) of ethyl O- (2-mesitylenesulfonyl) acetohydroxamate are placed in a flask in 30 ml of 1,4-dioxane. It is cooled to 0 ° C. and 13.5 ml (156.60 mmol) of perchloric acid (70% in water) are added. 10 ml of 1,4-dioxane are then added and then the medium is stirred vigorously for 2 hours 30 minutes at 0 ° C. The medium is then poured into 350 ml of ice water. The medium is left at 0 ° C. for 10 minutes and then the white solid formed is recovered by filtration on sintered glass (do not dry completely, the product is potentially explosive in the dry state). The white pasty solid obtained is washed with 350 ml of ice water and then taken up with 250 ml of 1,2-dichloroethane and 150 ml of brine cooled to 5 ° C. The organic phase is recovered and is filtered on a hydrophobic cartridge. The filtrate is recovered and 8.1 g (24.88 mmol) of 2- (4-bromopyridin-2-yl) -1- (4-chlorophenyl) are added dropwise to a cooled solution at 0 ° C. ethanone oxime (compound obtained in step 1.2) in 150 mL of 1,2-dichloroethane.

Après l'ajout, on laisse revenir et on agite à température ambiante pendant 3 heures. On ajoute ensuite successivement au milieu 250mL de dichlorométhane, 200mL d'eau et 100 mL d'une solution aqueuse NaOH (1N). On laisse agiter puis on décante. La phase organique est séparée et la phase aqueuse est extraite avec 2 fois 200 mL de dichlorométhane. Les phases organiques sont ensuite réunies, filtrées sur cartouche hydrophobe (Colonne d'extraction liquide/liquide 70 mL, Radleys®) puis mélangées avec 15 g de silice. Le filtrat est ensuite concentré sous pression réduite : on obtient une poudre marron que l'on utilise comme dépôt solide pour une chromatographie sur gel de silice en éluant avec un mélange de cyclohexane et de dichlorométhane (1/1). On obtient 5,8 g (75%) de composé sous forme d'un solide cotonneux légèrement jaune.
LC-MS : M+H = 307.
RMN-1H (DMSO) δ (ppm) : 7,0 (d, 1H) ; 7,1 (s, 1H) ; 7,6 (d, 2H) ; 8,0 (s, 1H) ; 8,1 (d, 2H) ; 8,7 (d, 1H).After the addition, allowed to return and stirred at room temperature for 3 hours. 250 ml of dichloromethane, 200 ml of water and 100 ml of a NaOH (1N) aqueous solution are then successively added to the medium. Let it shake and then decant. The organic phase is separated and the aqueous phase is extracted with twice 200 ml of dichloromethane. The organic phases are then combined, filtered on a hydrophobic cartridge (liquid / liquid extraction column 70 ml, Radleys®) and then mixed with 15 g of silica. The filtrate is then concentrated under reduced pressure to give a brown powder which is used as a solid deposit for chromatography on silica gel, eluting with a mixture of cyclohexane and dichloromethane (1/1). 5.8 g (75%) of compound is obtained in the form of a slightly yellow cottony solid.
LC-MS: M + H = 307.
1 H NMR (DMSO) δ (ppm): 7.0 (d, 1H); 7.1 (s, 1H); 7.6 (d, 2H); 8.0 (s, 1H); 8.1 (d, 2H); 8.7 (d, 1H).

1.4 3-[2-(4-Chlororophényl)pyrazolo[1,5-a]pyridin-5-yl]benzoate de méthyleMethyl 3- [2- (4-chlorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] benzoate

On place dans un ballon 0,235 g (0,76 mmol) de 5-bromo-2-(4-chlorophényl)pyrazolo[1,5-a]pyridine obtenu dans l'étape 1.3, 0,165 g (0,92 mmol) d'acide 3-méthoxycarbonylphénylboronique , 0,750 g (2,30 mmol) de carbonate de césium et 0,065 g (0,08 mmol) de [1,1'-bis(diphenylphosphino)ferrocène]dichloropalladium (II) en présence de 5 mL d'un mélange THF-eau (9/1). Le milieu est ensuite porté à 70°C pendant 1 h30 puis le milieu est remis à température ambiante et dilué avec 30 mL de dichlorométhane et 30 mL d'eau. Le milieu biphasique est filtré sur cartouche hydrophobe (Colonne d'extraction liquide/liquide 70 mL, Radleys®) puis le filtrat concentré sous pression réduite : le résidu obtenu est chromatographié sur gel de silice en éluant avec un mélange de cyclohexane et d'acétate d'éthyle (8/2). On obtient 0,200 g (72%) de composé attendu sous forme d'une poudre beige.
Point de fusion (°C) : 180-182
LC-MS : M+H = 363
RMN-1H (DMSO) δ (ppm) : 3,95 (s, 3H) ; 7,20 (s, 1H) ; 7,35 (d, 1H) ; 7,60 (d, 2H) ; 7,70 (t, 1H) ; de 8,00 à 8,20 (m, 5H) ; 8,35 (s, 1H) ; 8,85 (d, 1H).0.235 g (0.76 mmol) of 5-bromo-2- (4-chlorophenyl) pyrazolo [1,5- a ] pyridine obtained in step 1.3, 0.165 g (0.92 mmol) are placed in a flask. 3-methoxycarbonylphenylboronic acid, 0.750 g (2.30 mmol) of cesium carbonate and 0.065 g (0.08 mmol) of [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) in the presence of 5 mL of a THF-water mixture (9/1). The medium is then heated at 70 ° C. for 1 h 30 min then the medium is brought to room temperature and diluted with 30 ml of dichloromethane and 30 ml of water. The biphasic medium is filtered on a hydrophobic cartridge (liquid / liquid extraction column 70 ml, Radleys®) and then the filtrate is concentrated under reduced pressure: the residue obtained is chromatographed on silica gel, eluting with a mixture of cyclohexane and acetate of ethyl (8/2). 0.200 g (72%) of expected compound is obtained in the form of a beige powder.
Melting point (° C): 180-182
LC-MS: M + H = 363
1 H NMR (DMSO) δ (ppm): 3.95 (s, 3H); 7.20 (s, 1H); 7.35 (d, 1H); 7.60 (d, 2H); 7.70 (t, 1H); from 8.00 to 8.20 (m, 5H); 8.35 (s, 1H); 8.85 (d, 1H).

Exemple 2 : 3-[2-(4-Chlorophényl)pyrazolo[1,5-a]pyridin-5-yl]benzamide (composé 2 du tableau) Example 2 : 3- [2- (4-Chlorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] benzamide (Compound Compound 2) 2.1 3-[2-(4-Chlorophényl)pyrazolo[1,5-a]pyridin-5-yl]benzonitrile2.1 3- [2- (4-Chlorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] benzonitrile

0,850 g (2,76 mmol) de 5-bromo-2-(4-chlorophényl)pyrazolo[1,5-a]pyridine obtenu selon le protocole de l'étape 1.3 sont placés dans un ballon avec 0,490 g (3,33 mmol) d'acide 3-cyanophénylboronique, 2,70 g (8,29 mmol) de carbonate de césium et 0,225 g (0,26 mmol) de [1,1'-bis(diphenylphosphino)ferrocène]dichloropalladium (II) en présence de 20 mL d'un mélange THF-eau (9/1). Le milieu est ensuite porté à 75°C pendant 3 h avant de rajouter 0,245 g (1,66 mmol) d'acide 3-cyanophénylboronique, 1,35 g (4,14 mmol) de carbonate de césium et 0,115 g (0,14 mmol) de [1,1'-bis(diphenylphosphino)ferrocène]dichloropalladium (II) et d'agiter le milieu à 75°C pendant 1h30. Le milieu est ensuite dilué avec 100 mL d'acétate d'éthyle et 100 mL d'eau. La phase organique est ensuite récupérée et la phase aqueuse est extraite deux fois avec 100 mL d'acétate d'éthyle. Les phases organiques sont ensuite réunies avant d'être séchées sur sulfate de sodium et filtrées. Le filtrat est alors concentré sous pression réduite puis le résidu obtenu est dissout dans du tétrahydrofuranne et concentré sous pression réduite après ajout de 10g de silice. Le résidu est chromatographié sur gel de silice en éluant avec un mélange de cyclohexane et d'acétate d'éthyle (8/2). On obtient 0,185 g (20,2%) de composé attendu sous forme d'une poudre blanche.
LC-MS : M+H = 330
RMN-1H (DMSO) δ (ppm) : 7,19 (s, 1H) ; 7,37 (dd, 1H) ; 7,56 (m, 2H) ; 7,74 (t, 1H) ; 7,90 (m, 1H) ; 8,06 (m, 2H) ; de 8,15 à 8,24 (m, 2H) ; 8,35 (m, 1H) ; 8,82 (d, 1H).0.850 g (2.76 mmol) of 5-bromo-2- (4-chlorophenyl) pyrazolo [1,5-a] pyridine obtained according to the protocol of step 1.3 are placed in a flask with 0.490 g (3.33 g). mmol) of 3-cyanophenylboronic acid, 2.70 g (8.29 mmol) of cesium carbonate and 0.225 g (0.26 mmol) of [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) in presence of 20 mL of THF-water (9/1). The medium is then brought to 75 ° C. for 3 hours before adding 0.245 g (1.66 mmol) of 3-cyanophenylboronic acid, 1.35 g (4.14 mmol) of cesium carbonate and 0.115 g (0, 14 mmol) of [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) and stir the medium at 75 ° C for 1h30. The medium is then diluted with 100 ml of ethyl acetate and 100 ml of water. The organic phase is then recovered and the aqueous phase is extracted twice with 100 ml of ethyl acetate. The organic phases are then combined before being dried over sodium sulphate and filtered. The filtrate is then concentrated under reduced pressure and the residue obtained is dissolved in tetrahydrofuran and concentrated under reduced pressure after adding 10 g of silica. The residue is chromatographed on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (8/2). 0.185 g (20.2%) of the expected compound is obtained in the form of a white powder.
LC-MS: M + H = 330
1 H NMR (DMSO) δ (ppm): 7.19 (s, 1H); 7.37 (dd, 1H); 7.56 (m, 2H); 7.74 (t, 1H); 7.90 (m, 1H); 8.06 (m, 2H); from 8.15 to 8.24 (m, 2H); 8.35 (m, 1H); 8.82 (d, 1H).

2.2 3-[2-(4-Chlorophényl)pyrazolo[1,5-a]pyridin-5-yl]benzamide2.2 3- [2- (4-Chlorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] benzamide

0,150 g (0,45 mmol) de-[2-(4-chlorophényl)pyrazolo[1,5-a]pyridin-5-yl]benzonitrile obtenu dans l'étape 2.1 sont placés dans un ballon avec 5 mL de diméthylsulfoxide anhydre. Le milieu est alors refroidi vers 10°C et 0,100 mL (1,17 mmol) d'une solution d'eau oxygénée (35% dans l'eau) et 0,035 g (0,25 mmol) de carbonate de potassium sont ajoutés. Le milieu est remis progressivement à température ambiante et agité pendant 1 heure. On refroidit ensuite le milieu vers 5°C pour rajouter 0,500 mL (5,85 mmol) d'eau oxygénée et 0,250 g (1,78 mmol) de carbonate de potassium. Le milieu est ensuite agité pendant 1h30 à température ambiante avant d'être dilué dans 50 mL d'eau. On filtre le milieu sur verre fritté et on récupère une poudre que l'on chromatographie (par dépôt solide) sur gel de silice en éluant avec un mélange de dichlorométhane et de méthanol (9/1). On obtient 0,090 g (56,8%) de composé attendu sous forme d'une poudre blanche.
Point de fusion (°C) : 283-285
LC-MS : M+H = 348
RMN-1H (DMSO) δ (ppm) : 7,17 (s, 1H) ; 7,36 (dd, 1H) ; 7,47 (s, 1H) ; 7,56 (m, 2H) ; 7,61 (t, 1H) ; 7,94 (m, 1H) ; 8,00 (m, 1H) ; 8,07 (m, 2H) ; 8,11 (m, 1H) ; 8,15 (s, 1H) ; 8,32 (m, 1H) ; 8,82 (d, 1H).0.150 g (0.45 mmol) of [2- (4-chlorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] benzonitrile obtained in step 2.1 are placed in a flask with 5 mL of anhydrous dimethylsulfoxide. . The medium is then cooled to 10 ° C. and 0.100 ml (1.17 mmol) of a solution of hydrogen peroxide (35% in water) and 0.035 g (0.25 mmol) of potassium carbonate are added. The medium is gradually brought to room temperature and stirred for 1 hour. The medium is then cooled towards 5 ° C. to add 0.500 ml (5.85 mmol) of hydrogen peroxide and 0.250 g (1.78 mmol) of potassium carbonate. The medium is then stirred for 1 h 30 at room temperature before being diluted in 50 ml of water. The medium is filtered on sintered glass and a powder is recovered which is chromatographed (by solid deposition) on silica gel, eluting with a mixture of dichloromethane and methanol (9/1). 0.090 g (56.8%) of the expected compound is obtained in the form of a white powder.
Melting point (° C): 283-285
LC-MS: M + H = 348
1 H NMR (DMSO) δ (ppm): 7.17 (s, 1H); 7.36 (dd, 1H); 7.47 (s, 1H); 7.56 (m, 2H); 7.61 (t, 1H); 7.94 (m, 1H); 8.00 (m, 1H); 8.07 (m, 2H); 8.11 (m, 1H); 8.15 (s, 1H); 8.32 (m, 1H); 8.82 (d, 1H).

Exemple 3: 3-[2-(4-Chlorophényl)pyrazolo[1,5-a]pyridin-5-yl]-N,N-diméthylbenzamide (composé 3 du tableau) Example 3 3- [2- (4-Chlorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] -N, N- dimethylbenzamide (Compound Compound 3)

Sous courant d'azote, 0,900mL (1,80 mmol) d'une solution de diméthylamine (2M dans tetrahydrofuranne) et 8 mL de toluène sous placés dans un ballon. Le milieu est ensuite refroidi vers 0°C puis 0,900 mL (1,80 mmol) d'une solution de triméthylaluminium (2M dans toluène) sont ajoutés goutte à goutte. Après l'ajout, le milieu est agité vers 0°C pendant 25 minutes avant d'ajouter 0,200 g (0,55 mmol) de 3-[2-(4-chlororophényl)pyrazolo[1,5-a]pyridin-5-yl]benzoate de méthyle obtenu à l'étape 2.1. Le milieu est ensuite porté à 90°C pendant 3 heures avant d'être refroidi vers 0°C. Le milieu est alors hydrolyse par ajout goutte à goutte de 10 mL d'une solution d'acide chlorhydrique (1N). Après l'ajout, le milieu est remis à température ambiante puis dilué avec 60 mL de dichlorométhane et 60 mL d'eau. Le pH de la phase aqueuse est amené vers 11 à l'aide d'une solution de soude (1N) puis on filtre le milieu biphasique obtenu sur verre fritté garni de Célite. On récupère le filtrat que l'on passe sur cartouche hydrophobe (Colonne d'extraction liquide/liquide 70 mL, Radleys®). Le filtrat est récupéré et concentré sous pression réduite après ajout de 1,2 g de silice. Le résidu obtenu est chromatographié sur gel de silice en éluant avec un mélange de cyclohexane et d'acétate d'éthyle (3/7).Under a stream of nitrogen, 0.900 ml (1.80 mmol) of a solution of dimethylamine (2M in tetrahydrofuran) and 8 ml of toluene placed in a flask. The medium is then cooled to 0 ° C. and then 0.900 ml (1.80 mmol) of a solution of trimethylaluminium (2M in toluene) are added dropwise. After the addition, the medium is stirred at 0 ° C. for 25 minutes before adding 0.200 g (0.55 mmol) of 3- [2- (4-chlorophenyl) pyrazolo [1,5-a] pyridin-5 methyl] benzoate obtained in step 2.1. The medium is then heated at 90 ° C. for 3 hours before being cooled to 0 ° C. The medium is then hydrolysed by dropwise addition of 10 ml of a solution of hydrochloric acid (1N). After the addition, the medium is brought to ambient temperature and then diluted with 60 ml of dichloromethane and 60 ml of water. The pH of the aqueous phase is brought to 11 with a sodium hydroxide solution (1N) and the biphasic medium obtained on sintered glass filled with Celite is then filtered. The filtrate is recovered and passed through a hydrophobic cartridge (liquid / liquid extraction column 70 ml, Radleys®). The filtrate is recovered and concentrated under reduced pressure after adding 1.2 g of silica. The residue obtained is chromatographed on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (3/7).

On obtient 0,121 g (58,4%) de composé attendu sous forme d'une poudre blanche.
Point de fusion (°C) : 175-177
LC-MS : M+H = 376
RMN-1H (DMSO) δ (ppm) : 3,02 (d, 6H) ; 7,15 (s, 1H) ; 7,35 (dd, 1H) ; 7,46 (m, 1H) ; de 7,50 à 7,67 (m, 3H) ; 7,85 (m, 1H) ; 7,91 (m, 1H) ; de 8,00 à 8,15 (m, 3H) ; 8,80 (d, 1H).0.121 g (58.4%) of the expected compound is obtained in the form of a white powder.
Melting point (° C): 175-177
LC-MS: M + H = 376
1 H NMR (DMSO) δ (ppm): 3.02 (d, 6H); 7.15 (s, 1H); 7.35 (dd, 1H); 7.46 (m, 1H); from 7.50 to 7.67 (m, 3H); 7.85 (m, 1H); 7.91 (m, 1H); from 8.00 to 8.15 (m, 3H); 8.80 (d, 1H).

Exemple 4: 3-[2-(4-Chlorophényl)pyrazolo[1,5-a]pyridin-5-yl]-N-méthylbenzamide (composé 4 du tableau) Example 4: 3- [2- (4-Chlorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] -N-methylbenzamide (Compound Compound 4)

On procède suivant le mode opératoire décrit dans l'exemple 3. à partir de 0,200 g (0,55 mmol) de 3-[2-(4-chlororophényl)pyrazolo[1,5-a]pyridin-5-yl]benzoate de méthyle obtenu à l'étape 3.1, 0,900 mL (1,80 mmol) d'une solution de méthylamine (2M dans tetrahydrofuranne) et 0,900 mL (1,80 mmol) d'une solution de triméthylaluminium (2M dans toluène) dans 8 mL de toluène. Après chromatographie sur gel de silice en éluant avec un mélange de cyclohexane et d'acétate d'éthyle (1/1), on récupère 0,151 g (75,6%) de composé attendu sous forme d'une poudre blanche.
Point de fusion (°C) : 234-236
LC-MS : M+H = 362
RMN-1H (DMSO) δ (ppm) : 2,85 (d, 3H) ; 7,18 (s, 1H) ; 7,35 (m, 1H) ; de 7,51 à 7,68 (m, 3H) ; 7,90 (m, 1H) ; 8,00 (m, 1H) ; de 8,02 à 8,12 (m, 3H) ; 8,28 (m, 1H) ; 8,62 (m, 1H) ; 8,82 (d, 1H).The procedure described in Example 3 is carried out starting from 0.200 g (0.55 mmol) of 3- [2- (4-chlorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] benzoate. of methyl obtained in step 3.1, 0.900 mL (1.80 mmol) of a solution of methylamine (2M in tetrahydrofuran) and 0.900 mL (1.80 mmol) of a solution of trimethylaluminum (2M in toluene) in 8 mL of toluene. After chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1/1), 0.151 g (75.6%) of expected compound is recovered in the form of a white powder.
Melting point (° C): 234-236
LC-MS: M + H = 362
1 H NMR (DMSO) δ (ppm): 2.85 (d, 3H); 7.18 (s, 1H); 7.35 (m, 1H); from 7.51 to 7.68 (m, 3H); 7.90 (m, 1H); 8.00 (m, 1H); from 8.02 to 8.12 (m, 3H); 8.28 (m, 1H); 8.62 (m, 1H); 8.82 (d, 1H).

Exemple 5: 3-[2-(4-fluorophényl)pyrazolo[1,5-a]pyridin-5-yl]benzoate de méthyle (composé 5 du tableau) Example 5 Methyl 3- [2- (4-fluorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] benzoate (Compound Compound 5) 5.1 2-(4-bromopyridin-2-yl)-1-(4-fluorophényl)éthanone5.1 2- (4-Bromopyridin-2-yl) -1- (4-fluorophenyl) ethanone

Sous courant d'azote, 5,0 g (29,07 mmol) de 4-bromo-2-picoline et 10,2 g (60,95 mmol) de 4-fluorobenzoate d'éthyle sont placés dans un ballon et dissous dans 50 mL de tétrahydrofurane anhydre. On refroidit à 0°C et on ajoute goutte à goutte 70 mL (70 mmol) d'une solution d'hexaméthyldisilazane de lithium (1M dans le tétrahydrofurane). Après addition, le mélange est agité à température ambiante pendant 2h, refroidi à 5°C, puis 100 mL d'eau sont additionnés progressivement. Le milieu est ensuite dilué avec 250 mL d'acétate d'éthyle et 100 mL d'eau. La phase organique est séparée, la phase aqueuse est extraite deux fois avec 100 mL d'acétate d'éthyle. Les phases organiques sont ensuite réunies, séchées sur sulfate de sodium et filtrées. On ajoute ensuite au filtrat 15 g de silice, agite puis concentre sous pression réduite. La poudre obtenue est utilisée comme dépôt solide pour une chromatographie sur gel de silice avec pour éluant un mélange de cyclohexane et d'acétate d'éthyle (9/1). 7,5 g (88%) de composé sont obtenus sous forme d'une poudre jaune.
LC-MS : M+H = 294 (ratio cétone / énol: 43 / 57)
RMN-1H (DMSO) δ (ppm) : 4,56 (s, 2H) ; 6,34 (s, 1H) ; de 7,23 à 7,40 (m, 5H) ; 7,53 (d, 1H) ; 7,56 (m, 1H) ; 7,70 (d, 1H) ; de 7,81 à 7,92 (m, 2H) ; de 8,04 à 8,16 (m,2H) ; 8,29 (d, 1H) ; 8,37 (d, 1H) ; 15,0 (s, 1H).Under a stream of nitrogen, 5.0 g (29.07 mmol) of 4-bromo-2-picoline and 10.2 g (60.95 mmol) of ethyl 4-fluorobenzoate are placed in a flask and dissolved in a flask. 50 mL of anhydrous tetrahydrofuran. It is cooled to 0 ° C. and 70 ml (70 mmol) of a solution of lithium hexamethyldisilazane (1M in tetrahydrofuran) are added dropwise. After addition, the mixture is stirred at room temperature for 2 h, cooled to 5 ° C, then 100 mL of water are added gradually. The medium is then diluted with 250 ml of ethyl acetate and 100 ml of water. The organic phase is separated, the aqueous phase is extracted twice with 100 ml of ethyl acetate. The organic phases are then combined, dried over sodium sulphate and filtered. 15 g of silica are then added to the filtrate, the mixture is stirred and then concentrated under reduced pressure. The powder obtained is used as a solid deposit for chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (9/1). 7.5 g (88%) of compound are obtained in the form of a yellow powder.
LC-MS: M + H = 294 ( ketone / enol ratio: 43/57)
1 H NMR (DMSO) δ (ppm): 4.56 (s, 2H); 6.34 (s, 1H); from 7.23 to 7.40 (m, 5H); 7.53 (d, 1H); 7.56 (m, 1H); 7.70 (d, 1H); from 7.81 to 7.92 (m, 2H); from 8.04 to 8.16 (m, 2H); 8.29 (d, 1H); 8.37 (d, 1H); 15.0 (s, 1H).

5.2 2-(4-bromopyridin-2-yl)-1-(4-fluorophényl)éthanone oxime5.2 2- (4-bromopyridin-2-yl) -1- (4-fluorophenyl) ethanone oxime

7,5 g (24,26 mmol) de 2-(4-bromopyridin-2-yl)-1-(4-fluorophényl)éthanone sont placés dans un ballon contenant 100 mL d'éthanol absolu. 20 mL (247,78 mmol) de pyridine et 7,08 g (101,88 mmol) d'hydroxylamine monochlorhydrate sont ajoutés avant de laisser agiter le milieu pendant 3h à température ambiante. L'éthanol est ensuite évaporé sous vide et le résidu obtenu est repris avec 250 mL d'eau et 250 mL d'acétate d'éthyle. La phase organique est séparée, puis on extrait la phase aqueuse 5 fois avec 150 mL d'acétate d'éthyle. Les phases organiques sont ensuite réunies, séchées sur sulfate de sodium et concentrée sous vide. 7,82 g de composé sont obtenus.
LC-MS : M+H = 309
RMN 1H (DMSO-d6, δ en ppm): 4,26 (s, 2H) ; 7,19 (t, 2H) ; 7,50 (m, 2H) ; 7,75 (m, 2H) ; 8,33 (d, 1H) ; 11,50 (s, 1H). (obtention de l'oxime (E)).7.5 g (24.26 mmol) of 2- (4-bromopyridin-2-yl) -1- (4-fluorophenyl) ethanone are placed in a flask containing 100 ml of absolute ethanol. 20 mL (247.78 mmol) of pyridine and 7.08 g (101.88 mmol) of hydroxylamine monohydrochloride are added before stirring the medium for 3h at room temperature. The ethanol is then evaporated under vacuum and the the residue obtained is taken up in 250 ml of water and 250 ml of ethyl acetate. The organic phase is separated, and then the aqueous phase is extracted 5 times with 150 ml of ethyl acetate. The organic phases are then combined, dried over sodium sulphate and concentrated in vacuo. 7.82 g of compound are obtained.
LC-MS: M + H = 309
1H NMR (DMSO-d6, δ in ppm): 4.26 (s, 2H); 7.19 (t, 2H); 7.50 (m, 2H); 7.75 (m, 2H); 8.33 (d, 1H); 11.50 (s, 1H). (obtaining the oxime (E)).

5.3 5-bromo-2-(4-fluororophényl)pyrazolo[1,5-a]pyridine5.3 5-Bromo-2- (4-fluorophenyl) pyrazolo [1,5- a ] pyridine

7,82 g (25,50 mmol) de 2-(4-bromopyridin-2-yl)-1-(4-fluorophényl)éthanone oxime sont placés dans un ballon et dissous dans 400 mL de 1,2-dichloroéthane. Une solution de O-(mésitylènesulfonyl)hydroxylamine (0,27 M dans le 1,2-dichloroéthane - composé obtenu selon le protocole décrit en 1.3) est ajoutée goutte à goutte au milieu refroidi vers 0°C. Après l'ajout, le milieu est agité à température ambiante pendant 1h30. Le milieu est ensuite dilué avec 200mL d'eau et 200mL d'une solution de soude (1N). Le milieu biphasique est agité puis décanté. La phase organique est séparée, puis la phase aqueuse est extraite 4 fois avec 200 mL de dichlorométhane. Les phases organiques sont ensuite réunies, séchées sur sulfate de sodium et filtrées. On ajoute ensuite au filtrat 15 g de silice puis concentre sous pression réduite. La poudre obtenue est utilisée comme dépôt solide pour une chromatographie sur gel de silice avec pour éluant un mélange de cyclohexane et de dichlorométhane (1/1). 5,06 g (68%) de composé sont obtenus sous forme d'une poudre cotonneuse blanche.
LC-MS : M+H = 291
RMN 1H (DMSO-d6, δ en ppm): de 7,00 à 7,10 (m, 2H) ; 7,45 (m, 2H) ; 8,05 (m, 3H) ; 8,70 (d, 1H).7.82 g (25.50 mmol) of 2- (4-bromopyridin-2-yl) -1- (4-fluorophenyl) ethanone oxime are placed in a flask and dissolved in 400 ml of 1,2-dichloroethane. A solution of O- (mesitylenesulfonyl) hydroxylamine (0.27 M in 1,2-dichloroethane - compound obtained according to the protocol described in 1.3) is added dropwise to the cooled medium at 0 ° C. After the addition, the medium is stirred at ambient temperature for 1 h 30. The medium is then diluted with 200 ml of water and 200 ml of a sodium hydroxide solution (1N). The biphasic medium is stirred and decanted. The organic phase is separated, and then the aqueous phase is extracted 4 times with 200 mL of dichloromethane. The organic phases are then combined, dried over sodium sulphate and filtered. 15 g of silica are then added to the filtrate and then concentrated under reduced pressure. The powder obtained is used as a solid deposit for chromatography on silica gel with a mixture of cyclohexane and dichloromethane (1/1) as eluent. 5.06 g (68%) of compound are obtained in the form of a white cottony powder.
LC-MS: M + H = 291
1H NMR (DMSO-d6, δ in ppm): from 7.00 to 7.10 (m, 2H); 7.45 (m, 2H); 8.05 (m, 3H); 8.70 (d, 1H).

5.4 3-[2-(4-fluorophényl)pyrazolo[1,5-a]pyridin-5-yl]benzoate de méthyleMethyl 3- [2- (4-fluorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] benzoate

Sous courant d'azote sont introduits 0,400 g (1,37 mmol) de 5-bromo-2-(4-fluorophényl)pyrazolo[1,5-a]pyridine obtenu à l'étape 5.3., 0,300 g (1,67 mmol) d'acide 3-méthoxycarbonylphénylboronique, 1,330 g (4,08 mmol) de carbonate de césium dans 5 mL d'un mélange 9/1 de tétrahydrofurane et d'eau. 0,11 g (0,13 mmol) de [1,1'-bis(diphenylphosphino)ferrocène]dichloropalladium (II) sont ajoutés et le milieu est chauffé à 70°C pendant 4 heures. Le milieu est ensuite remis à température ambiante puis dilué avec 40 mL de dichlorométhane et 40 mL d'eau. Le milieu est ensuite filtré sur cartouche hydrophobe (Colonne d'extraction liquide/liquide 70 mL, Radleys®), la phase organique est récupérée et concentrée sous pression réduite après avoir ajouté 2 g de silice. Le résidu par chromatographie sur gel de silice en éluant avec un mélange de cyclohexane et d'acétate d'éthyle (9/1). On obtient 0,340 g (71%) de produit attendu sous la forme d'une poudre blanche.
Point de fusion (°C) : 162-164
LC-MS : M+H = 347
RMN-1H (DMSO) δ (ppm) : 3,95 (s, 3H) ; 7,15 (s, 1H) ; de 7,30 à 7,38 (m, 3H) ; 7,70 (t, 1H) ; de 8,00 à 8,15 (m, 5H) ; 8,35 (m, 1H) ; 8,80 (d, 1H).A stream of nitrogen is charged with 0.400 g (1.37 mmol) of 5-bromo-2- (4-fluorophenyl) pyrazolo [1,5- a ] pyridine obtained in step 5.3., 0.300 g (1.67 g) mmol) of 3-methoxycarbonylphenylboronic acid, 1.330 g (4.08 mmol) of cesium carbonate in 5 ml of a 9/1 mixture of tetrahydrofuran and water. 0.11 g (0.13 mmol) of [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) are added and the medium is heated at 70 ° C. for 4 hours. The medium is then brought to ambient temperature and then diluted with 40 ml of dichloromethane and 40 ml of water. The medium is then filtered on a hydrophobic cartridge (liquid / liquid extraction column 70 ml, Radleys®), the organic phase is recovered and concentrated under reduced pressure after adding 2 g of silica. The residue by chromatography on silica gel eluting with a mixture of cyclohexane and ethyl acetate (9/1). 0.340 g (71%) of expected product is obtained in the form of a white powder.
Melting point (° C): 162-164
LC-MS: M + H = 347
1 H NMR (DMSO) δ (ppm): 3.95 (s, 3H); 7.15 (s, 1H); from 7.30 to 7.38 (m, 3H); 7.70 (t, 1H); from 8.00 to 8.15 (m, 5H); 8.35 (m, 1H); 8.80 (d, 1H).

Exemple 6 3-[2-(4-Fluorophényl)pyrazolo[1,5-a]pyridin-5-yl]-N-méthylbenzamide (composé 6 du tableau) Example 6 3- [2- (4-Fluorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] -N- methylbenzamide (Compound Compound 6)

On procède suivant le mode opératoire décrit dans l'exemple3. à partir de 0,200 g (0,58 mmol) de 3-[2-(4-fluorophényl)pyrazolo[1,5-a]pyridin-5-yl]benzoate de méthyle obtenu à l'étape 7.4, 1,00 mL (2,00 mmol) d'une solution de méthylamine (2M dans tetrahydrofuranne) et 1,00 mL (2,00 mmol) d'une solution de triméthylaluminium (2M dans toluène) dans 8 mL de toluène. Après chromatographie sur gel de silice en éluant avec un mélange de cyclohexane et d'acétate d'éthyle (1/1), on récupère 0,235 g (67,7%) de composé attendu sous forme d'une poudre blanche.
Point de fusion (°C) : 214-216
LC-MS : M+H = 346
RMN-1H (DMSO) δ (ppm) : 2,85 (d, 3H) ; 7,15 (s, 1H) ; de 7,26 à 7,46 (m, 3H) ; 7,62 (m, 1H) ; 7,90 (m, 1H) ; 8,00 (m, 1H) ; de 8,05 à 8,21 (m, 3H) ; 8,29 (m, 1H) ; 8,60 (m, 1H) ; 8,82 (d, 1H).The procedure is as described in Example 3. from 0.200 g (0.58 mmol) of methyl 3- [2- (4-fluorophenyl) pyrazolo [1,5-a] pyridin-5-yl] benzoate obtained in step 7.4, 1.00 mL (2.00 mmol) of a solution of methylamine (2M in tetrahydrofuran) and 1.00 mL (2.00 mmol) of a solution of trimethylaluminium (2M in toluene) in 8 mL of toluene. After chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1/1), 0.235 g (67.7%) of the expected compound is recovered in the form of a white powder.
Melting point (° C): 214-216
LC-MS: M + H = 346
1 H NMR (DMSO) δ (ppm): 2.85 (d, 3H); 7.15 (s, 1H); from 7.26 to 7.46 (m, 3H); 7.62 (m, 1H); 7.90 (m, 1H); 8.00 (m, 1H); from 8.05 to 8.21 (m, 3H); 8.29 (m, 1H); 8.60 (m, 1H); 8.82 (d, 1H).

Exemple 7: 3-[2-(4-Fluorophényl)pyrazolo[1,5-a]pyridin-5-yl]-2,N-diméthyl benzamide (composé 10 du tableau) Example 7: 3- [2- (4-Fluorophenyl) pyrazolo [1,5-a] pyridin-5-yl] -2, N-dimethyl benzamide (compound 10 of Table) 7.1 2-(4-Fluorophényl)-5-(4,4,5,5-tétraméthyl-[1,3,2]dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (Composé VI-1)7.1 2- (4-Fluorophenyl) -5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) pyrazolo [1,5-a] pyridine (Compound VI-1)

1,00 g (3,43 mmol) de 5-bromo-2-(4-fluorophényl)pyrazolo[1,5-a]pyridine obtenus tel qu'en 7.3 sont placés en présence de 1,05 g (4,13 mmol) de bis(pinacolato)dibore, de 1,00 g (10,19 mmol) d'acétate de potassium et 0,280 g (0,34 mmol) de [1,1'-bis(diphénylphosphino)ferrocène]dichloropalladium (II) dans 14 mL de dioxanne. Le milieu obtenu est irradié par micro-onde à 140°C pendant 20 minutes avant d'être dilué avec 100 mL de dichlorométhane et 100 mL d'eau. On filtre ensuite le milieu biphasique sur cartouche hydrophobe (Colonne d'extraction liquide/liquide 70 mL, Radleys®). La phase organique est récupérée et concentrée sous pression réduite après avoir ajouté 4 g de silice. Le résidu obtenu est chromatographié sur gel de silice en éluant avec un mélange de cyclohexane et d'acétate d'éthyle (9/1).1.00 g (3.43 mmol) of 5-bromo-2- (4-fluorophenyl) pyrazolo [1,5-a] pyridine obtained as in 7.3 are placed in the presence of 1.05 g (4.13 g). mmol) of bis (pinacolato) diborone, 1.00 g (10.19 mmol) of potassium acetate and 0.280 g (0.34 mmol) of [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II ) in 14 mL of dioxane. The medium obtained is irradiated by microwave at 140 ° C. for 20 minutes before being diluted with 100 ml of dichloromethane and 100 ml of water. The biphasic medium is then filtered on a hydrophobic cartridge (liquid / liquid extraction column 70 ml, Radleys®). The sentence organic is recovered and concentrated under reduced pressure after adding 4 g of silica. The residue obtained is chromatographed on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (9/1).

On obtient 0,992 g (85,4%) de composé attendu sous forme d'une poudre rosée.
LC-MS : M+H = 338 (dégradation sur colonne en acide boronique M+H= 257)
RMN-1H (DMSO) δ (ppm) : 1,35 (s, 12H) ; 7,00 (m, 1H) ; 7,19 (s, 1H) ; 7,34 (t, 2H) ; 8,05 (m, 3H) ; 8,69 (d, 1 H).0.992 g (85.4%) of expected compound is obtained in the form of a pink powder.
LC-MS: M + H = 338 (column degradation to boronic acid M + H = 257)
1 H NMR (DMSO) δ (ppm): 1.35 (s, 12H); 7.00 (m, 1H); 7.19 (s, 1H); 7.34 (t, 2H); 8.05 (m, 3H); 8.69 (d, 1H).

7.2 3-Bromo-2,N-diméthylbenzamide7.2 3-Bromo-2, N- dimethylbenzamide

0,500 g (2,33 mmol) d'acide 3-bromo-2-méthylbenzoïque sont placés dans un ballon en présence de 1,51 mL (10,83 mmol) de triéthylamine, 0,408 g (3,02 mmol) de N-hydroxybenzotriazole monohydrate, 0,579 g (3,02 mmol) de 1-(3-diméthylaminopropyl)-3-éthylcarbodiimide monochlorhydrate et 5 mL de dichlorométhane. Le milieu est agité à température ambiante pendant 1 heure puis on ajoute 1,51 mL (3,02 mmol) d'une solution de méthylamine (2M dans tétrahydrofuranne). Le milieu est agité toute une nuit à température ambiante puis on rajoute 0,5 mL (1 mmol) de solution de méthylamine et on laisse agiter pendant toute une nuit. Le milieu est ensuite concentré sous pression réduite puis on ajoute au milieu 5 mL de dichlorométhane et 0,390 mL (2,99 mmol) de chloroformate d'isobutyle. Le milieu est à nouveau agité toute une nuit avant d'être dilué avec 7 mL de dichlorométhane et 7 mL d'eau. Le milieu est alors filtré sur cartouche hydrophobe (Colonne d'extraction liquide/liquide 70 mL, Radleys®). La phase organique est récupérée et concentrée sous pression réduite.0.500 g (2.33 mmol) of 3-bromo-2-methylbenzoic acid are placed in a flask in the presence of 1.51 ml (10.83 mmol) of triethylamine, 0.408 g (3.02 mmol) of N- hydroxybenzotriazole monohydrate, 0.579 g (3.02 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide monohydrochloride and 5 mL of dichloromethane. The medium is stirred at ambient temperature for 1 hour and then 1.51 ml (3.02 mmol) of a solution of methylamine (2M in tetrahydrofuran) are added. The medium is stirred overnight at room temperature and then 0.5 ml (1 mmol) of methylamine solution are added and the mixture is stirred overnight. The medium is then concentrated under reduced pressure and then 5 ml of dichloromethane and 0.390 ml (2.99 mmol) of isobutyl chloroformate are added to the medium. The medium is again stirred overnight before being diluted with 7 mL of dichloromethane and 7 mL of water. The medium is then filtered on a hydrophobic cartridge (liquid / liquid extraction column 70 ml, Radleys®). The organic phase is recovered and concentrated under reduced pressure.

On obtient 0,298 g (56,2%) de composé attendu sous forme d'une poudre blanche.
LC-MS : M+H = 228
RMN 1H (DMSO) δ (ppm): 2,31 (s, 3H) ; 2,80 (d, 3H) ; de 7,05 à 7,35 (m, 2H) ; 7,68 (m, 1 H) ; 8,32 (s él., 1 H).0.298 g (56.2%) of expected compound is obtained in the form of a white powder.
LC-MS: M + H = 228
1 H NMR (DMSO) δ (ppm): 2.31 (s, 3H); 2.80 (d, 3H); from 7.05 to 7.35 (m, 2H); 7.68 (m, 1H); 8.32 (s, 1 H).

7.3 3-[2-(4-Fluorophényl)pyrazolo[1,5-a]pyridin-5-yl]-4,N-diméthylbenzamide7.3 3- [2- (4-Fluorophenyl) pyrazolo [1,5-a] pyridin-5-yl] -4, N -diméthylbenzamide

On place 0,150g (0,44 mmol) de 2-(4-fluorophényl)-5-(4,4,5,5-tétraméthyl-[1,3,2]dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine obtenu dans l'étape 7.1, 0,144 g (0,63 mmol) de 3-bromo-2,N-diméthylbenzamide obtenu dans l'étape 10.2 avec 0,434 g (1,33 mmol) de carbonate de césium et 0,036 g (0,044 mmol) de [1,1'-bis(diphénylphosphino)ferrocène]dichloropalladium (II) dans 5 mL d'un mélange 9/1 de tétrahydrofurane et d'eau. Le milieu est agité à 60°C pendant toute une nuit. Le milieu est ensuite dilué avec 50 mL de dichlorométhane et 50 mL d'eau. Le milieu biphasique est alors filtré sur cartouche hydrophobe (Colonne d'extraction liquide/liquide 70 mL, Radleys®). La phase organique est récupérée et concentrée sous pression réduite après avoir ajouté 1,5 g de silice. Le résidu obtenu est chromatographié sur gel de silice en éluant avec un mélange de cyclohexane et d'acétate d'éthyle (1/1).0.150 g (0.44 mmol) of 2- (4-fluorophenyl) -5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) pyrazolo [1,5 a) pyridine obtained in step 7.1, 0.144 g (0.63 mmol) of 3-bromo-2, N- dimethylbenzamide obtained in step 10.2 with 0.434 g (1.33 mmol) of cesium carbonate and 0.036 g g (0.044 mmol) of [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) in 5 mL of a 9/1 mixture of tetrahydrofuran and water. The medium is stirred at 60 ° C overnight. The medium is then diluted with 50 ml of dichloromethane and 50 ml of water. The biphasic medium is then filtered on hydrophobic cartridge (Liquid / liquid extraction column 70 mL, Radleys®). The organic phase is recovered and concentrated under reduced pressure after adding 1.5 g of silica. The residue obtained is chromatographed on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1/1).

On obtient 0,103 g (65%) de composé attendu sous forme d'une poudre blanche.
Point de fusion (°C) : 240-242
LC-MS : M+H = 360
RMN 1H (DMSO) δ (ppm): 2,37 (s, 3H) ; 2,80 (d, 3H) ; 6,86 (d, 1H) ; 7,10 (s, 1H) ; de 7,33 à 7,44 (m, 5H) ; 7,63 (s, 1H) ; 8,10 (m, 2H) ; 8,28 (s, 1H) ; 8,76 (d, 1H).0.103 g (65%) of expected compound is obtained in the form of a white powder.
Melting point (° C): 240-242
LC-MS: M + H = 360
1 H NMR (DMSO) δ (ppm): 2.37 (s, 3H); 2.80 (d, 3H); 6.86 (d, 1H); 7.10 (s, 1H); from 7.33 to 7.44 (m, 5H); 7.63 (s, 1H); 8.10 (m, 2H); 8.28 (s, 1H); 8.76 (d, 1H).

Exemple 8: N-Cyclopropyl-3-[2-(4-fluorophényl)pyrazolo[1,5-a]pyridin-5-yl]benzamide (composé 15 du tableau) Example 8 : N- Cyclopropyl-3- [2- (4-fluorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] benzamide (Table Compound 15)

0,0382 g (0,67 mmol) de cyclopropylamine sont dilués avec 10 mL de tétrahydrofuranne anhydre. On ajoute ensuite progressivement 0,0859 g (0,33 mmol) de DABAL (adduit double de triméthylaluminium avec du 1,4-diazabicyclo[2.2.2]octane) avant de laisser agiter le milieu pendant 1 heure. 0,145 g (0,42 mmol) de 3-[2-(4-fluorophényl)pyrazolo[1,5-a]pyridin-5-yl]benzoate de méthyle obtenu selon le protocole 5.4 sont alors ajoutés avant d'irradier le milieu réactionnel dans un microondes 2 fois 30 minutes à 130°C. Le milieu est ensuite hydrolysé vers 5°C à l'aide de 5 mL d'eau et de 5 mL d'une solution aqueuse d'acide chlorhydrique (1N). Après l'hydrolyse, le milieu est dilué avec 50 mL d'eau et 50 mL de dichlorométhane puis filtré sur cartouche hydrophobe (Colonne d'extraction liquide/liquide 70 mL, Radleys®). La phase organique est récupérée et concentrée sous pression réduite après avoir ajouté 1,5 g de silice. Le résidu obtenu est chromatographié sur gel de silice en éluant avec un mélange de cyclohexane et d'acétate d'éthyle (6/4).0.0382 g (0.67 mmol) of cyclopropylamine are diluted with 10 mL of anhydrous tetrahydrofuran. 0.0859 g (0.33 mmol) of DABAL (double adduct of trimethylaluminium with 1,4-diazabicyclo [2.2.2] octane) are then gradually added before stirring the medium for 1 hour. 0.145 g (0.42 mmol) of methyl 3- [2- (4-fluorophenyl) pyrazolo [1,5-a] pyridin-5-yl] benzoate obtained according to the protocol 5.4 are then added before irradiating the medium. Reaction in a microwave 2 times 30 minutes at 130 ° C. The medium is then hydrolysed at about 5 ° C. using 5 ml of water and 5 ml of an aqueous solution of hydrochloric acid (1N). After the hydrolysis, the medium is diluted with 50 ml of water and 50 ml of dichloromethane and then filtered on a hydrophobic cartridge (liquid / liquid extraction column 70 ml, Radleys®). The organic phase is recovered and concentrated under reduced pressure after adding 1.5 g of silica. The residue obtained is chromatographed on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (6/4).

On obtient 0,112 g (72,3%) de composé attendu sous forme d'une poudre blanche.
Point de fusion (°C) : 179-181
LC-MS : M+H = 372
RMN 1H (DMSO) δ (ppm): de 0,60 à 0,80 (m, 4H) ; 3,92 (m, 1H) ; 7,15 (s, 1H) ; de 7,30 à 7,39 (m, 3H) ; 7,61 (t, 1H) ; 7,88 (d, 1 H) ; 7,98 (d, 1H) ; 8,10 (m, 3H) ; 8,22 (s, 1H) ; 8,57 (m, 1H) ; 8,81 (d, 1H).0.112 g (72.3%) of the expected compound is obtained in the form of a white powder.
Melting point (° C): 179-181
LC-MS: M + H = 372
1 H NMR (DMSO) δ (ppm): 0.60 to 0.80 (m, 4H); 3.92 (m, 1H); 7.15 (s, 1H); from 7.30 to 7.39 (m, 3H); 7.61 (t, 1H); 7.88 (d, 1H); 7.98 (d, 1H); 8.10 (m, 3H); 8.22 (s, 1H); 8.57 (m, 1H); 8.81 (d, 1H).

Exemple 9: {3-[2-(4-Fluorophényl)pyrazolo[1,5-a]pyridin-5-yl]phényl}-(3-hydroxypyrrolidin-1-yl)méthanone (composé 22 du tableau) Example 9 : {3- [2- (4-Fluorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] phenyl} - (3-hydroxypyrrolidin-1-yl) methanone (Compound 22 of Table)

0,100 g (0,30 mmol) d'acide 3-[2-(4-fluorophényl)pyrazolo[1,5-a]pyridin-5-yl]benzoïque préparés comme dans l'exemple 8 sont placés dans un ballon en présence de 0,170 mL (1,20 mmol) de triéthylamine et 20 mL de dichlorométhane. On ajoute alors 0,051 µL (0,39 mmol) de chlorformate d'isobutyle et on laisse agiter le milieu à température ambiante pendant 2 heures. 0,0341 g (0,39 mmol) de 3-hydroxypyrrolidine sont ajoutés au milieu et on laisse agiter à nouveau à température ambiante pendant 2 heures. Le milieu est ensuite dilué avec 50 mL d'eau et 50 mL de dichlorométhane. On filtre alors le milieu biphasique sur cartouche hydrophobe (Colonne d'extraction liquide/liquide 70 mL, Radleys®). La phase organique est récupérée et concentrée sous pression réduite après avoir ajouté 1 g de silice. Le résidu obtenu est chromatographié sur gel de silice en éluant avec un mélange de cyclohexane et d'acétate d'éthyle (6/4).0.100 g (0.30 mmol) of 3- [2- (4-fluorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] benzoic acid prepared as in Example 8 are placed in a flask in the presence of 0.170 mL (1.20 mmol) of triethylamine and 20 mL of dichloromethane. 0.051 μL (0.39 mmol) of isobutyl chlorformate are then added and the medium is stirred at room temperature for 2 hours. 0.0341 g (0.39 mmol) of 3-hydroxypyrrolidine are added to the medium and allowed to stir again at room temperature for 2 hours. The medium is then diluted with 50 ml of water and 50 ml of dichloromethane. The biphasic medium is then filtered on a hydrophobic cartridge (liquid / liquid extraction column 70 ml, Radleys®). The organic phase is recovered and concentrated under reduced pressure after adding 1 g of silica. The residue obtained is chromatographed on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (6/4).

On obtient 0,063 g (50%) de composé attendu sous forme d'une cire jaune pâle.
Point de fusion (°C) : 173-175
LC-MS : M+H = 402
RMN 1H (DMSO) δ (ppm): de 1,65 à 2,05 (m, 2H) ; de 3,40 à 3,70 (m, 4H) ; 4,32 (d, 1h) ; 5,00 (d, 1H) ; 7,11 (s, 1H) ; 7,32 (m, 3H) ; 7,60 (m, 2H) ; 7,93 (d, 2H) ; 8,08 (m, 3H) ; 8,77 (d, 1H).0.063 g (50%) of the expected compound is obtained in the form of a pale yellow wax.
Melting point (° C): 173-175
LC-MS: M + H = 402
1 H NMR (DMSO) δ (ppm): from 1.65 to 2.05 (m, 2H); from 3.40 to 3.70 (m, 4H); 4.32 (d, 1h); 5.00 (d, 1H); 7.11 (s, 1H); 7.32 (m, 3H); 7.60 (m, 2H); 7.93 (d, 2H); 8.08 (m, 3H); 8.77 (d, 1H).

Exemple 10 : N-Méthyl-3-(2-p-tolylpyrazolo[1,5-a]pyridin-5-yl)benzamide (composé 328du tableau) Example 10 : N- methyl-3- (2-p-tolylpyrazolo [1,5- a ] pyridin-5-yl) benzamide (Compound 328) 10.1 2-(4-Bromo-pyridin-2-yl)-1-p-tolyléthanone10.1 2- (4-Bromo-pyridin-2-yl) -1-p-tolylethanone

Sous courant d'azote, 1 g (5,81 mmol) de 4-bromo-2-méthylpyridine et 1,75 g (11,60 mmol) de 4-méthylbenzoate de méthyle sont placés dans un ballon et dissous dans 30 mL de tétrahydrofurane anhydre. On refroidit à 5°C et on ajoute goutte à goutte 14 mL (14 mmol) d'une solution d'hexaméthyldisilazane de lithium (1M dans le tétrahydrofurane). Après addition, le mélange est agité à température ambiante pendant 2h30, puis refroidi à 5°C, avant d'ajouter progressivement 20 mL d'eau. Le milieu est ensuite dilué avec 200 mL d'acétate d'éthyle et 200 mL d'eau. La phase organique est séparée, séchée sur sulfate de sodium et filtrée. On ajoute ensuite au filtrat 5 g de silice avant le concentrer sous pression réduite. La poudre obtenue est utilisée comme dépôt solide pour une chromatographie sur gel de silice avec pour éluant un mélange de cyclohexane et d'acétate d'éthyle (95/5), on obtient 1,03 g (61%) de composé sous forme d'une poudre jaune.
LC-MS : M+H = 290Under a stream of nitrogen, 1 g (5.81 mmol) of 4-bromo-2-methylpyridine and 1.75 g (11.60 mmol) of methyl 4-methylbenzoate are placed in a flask and dissolved in 30 ml of anhydrous tetrahydrofuran. It is cooled to 5 ° C. and 14 ml (14 mmol) of a solution of lithium hexamethyldisilazane (1M in tetrahydrofuran) are added dropwise. After addition, the mixture is stirred at room temperature for 2 h 30, then cooled to 5 ° C, before gradually adding 20 ml of water. The medium is then diluted with 200 mL of ethyl acetate and 200 mL of water. The organic phase is separated, dried over sodium sulfate and filtered. 5 g of silica are then added to the filtrate before being concentrated under reduced pressure. The powder obtained is used as a solid deposit for chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (95/5) to give 1.03 g (61%) of compound in the form of a yellow powder.
LC-MS: M + H = 290

10.2 4-Bromo-2-(3-p-tolyl-2H-azirin-2-yl)pyridine10.2 4-Bromo-2- (3-p-tolyl-2H-azirin-2-yl) pyridine

On place 1,03 g de 2-(4-bromo-pyridin-2-yl)-1-p-tolyléthanone obtenu à l'étape 13.1 dans un ballon avec 0,99 g (14,2 mmol) d'hydroxylamine monochlorhydrate, 3mL (37 mmol) de pyridine et 100 mL d'éthanol. On laisse agiter toute une nuit puis on concentre sous pression réduite le milieu réactionnel. Le résidu obtenu est alors repris avec 200 mL d'acétate d'éthyle et 200 mL d'eau. La phase organique est récupérée, séchée sur sulfate de sodium puis concentrée sous pression réduite. 1,10 g de composé sont récupérés et dissous dans un ballon contenant 0,660 mL (4,74 mmol) de triéthylamine et 30 mL de dichlorométhane. Le milieu réactionnel est ensuite refroidi vers 5°C puis 0,200 mL (1,42 mmol) d'anhydride de l'acide trifluoroacétique sont ajoutés goutte à goutte. Le milieu est ensuite agité à température ambiante pendant 3 heures avant d'être hydrolyse avec 100 mL d'eau. Le milieu est ensuite agité pendant 10 minutes avant d'être filtré sur cartouche hydrophobe (Colonne d'extraction liquide/liquide 70 mL, Radleys®). On ajoute ensuite au filtrat 1,2 g de silice avant de le concentrer sous pression réduite. La poudre obtenue est utilisée comme dépôt solide pour une chromatographie sur gel de silice avec pour éluant un mélange de cyclohexane et d'acétate d'éthyle (95/5). On récupère 0,746 g (77%) de composé attendu sous forme d'une poudre blanche.
RMN-1H (DMSO) δ (ppm) : 2,42 (d, 3H) ; 3,45 (s, 1H) ; de 7,42 à 7,58 (m, 4H) ; 7,78 (m, 2H) ; 8,30 (d, 1 H).1.03 g of 2- (4-bromo-pyridin-2-yl) -1-p-tolylethanone obtained in step 13.1 are placed in a flask with 0.99 g (14.2 mmol) of hydroxylamine monohydrochloride, 3 mL (37 mmol) of pyridine and 100 mL of ethanol. Stirring is allowed overnight and then the reaction medium is concentrated under reduced pressure. The residue obtained is then taken up with 200 mL of ethyl acetate and 200 mL of water. The organic phase is recovered, dried over sodium sulfate and then concentrated under reduced pressure. 1.10 g of compound are recovered and dissolved in a flask containing 0.660 ml (4.74 mmol) of triethylamine and 30 ml of dichloromethane. The reaction medium is then cooled to 5 ° C. and 0.200 ml (1.42 mmol) of trifluoroacetic acid anhydride are added dropwise. The medium is then stirred at room temperature for 3 hours before being hydrolyzed with 100 ml of water. The medium is then stirred for 10 minutes before being filtered on a hydrophobic cartridge (liquid / liquid extraction column 70 ml, Radleys®). 1.2 g of silica are then added to the filtrate before being concentrated under reduced pressure. The powder obtained is used as a solid deposit for chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (95/5). 0.746 g (77%) of expected compound is recovered in the form of a white powder.
1 H NMR (DMSO) δ (ppm): 2.42 (d, 3H); 3.45 (s, 1H); 7.42 to 7.58 (m, 4H); 7.78 (m, 2H); 8.30 (d, 1H).

10.3 5-Bromo-2-p-tolyl-pyrazolo[1,5-a]pyridine10.3 5-Bromo-2-p-tolyl-pyrazolo [1,5-a] pyridine

0,746 g de 4-bromo-2-(3-p-tolyl-2H-azirin-2-yl)pyridine obtenue à l'étape 13.2 sont dissous en présence de 6,6 mg (0,052 mmol) de chlorure de fer (II) dans 30 mL de 1,2-diméthoxyéthane. Le milieu est alors porté à reflux pendant 6 heures. On rajoute ensuite 10 mg (0,078 mmol) de chlorure de fer (II) et on laisse ensuite agiter à nouveau à reflux pendant 3 heures. Le milieu est alors dilué avec 50 mL d'acétate d'éthyle et 50 mL d'eau. La phase organique est ensuite récupérée, séchée sur sulfate de sodium puis filtrée. On ajoute ensuite au filtrat 2 g de silice avant de le concentrer sous pression réduite. La poudre obtenue est utilisée comme dépôt solide pour une chromatographie sur gel de silice avec pour éluant un mélange de cyclohexane et d'acétate d'éthyle (85/15). On récupère 0,534g (71%) de composé attendu sous forme d'une poudre jaune.
LC-MS : M+H = 287
RMN-1H (DMSO) δ (ppm) : 2,48 (m, 3H) ; 7,00 (m, 2H) ; 7,32 (m, 2H) ; 7,88 (m, 2H) ; 8,00 (m, 1 H) ; 8,68 (d, 1H).0.746 g of 4-bromo-2- (3-p-tolyl-2H-azirin-2-yl) pyridine obtained in step 13.2 are dissolved in the presence of 6.6 mg (0.052 mmol) of iron (II) chloride. ) in 30 mL of 1,2-dimethoxyethane. The medium is then refluxed for 6 hours. 10 mg (0.078 mmol) of iron (II) chloride are then added and the mixture is then stirred again at reflux for 3 hours. The medium is then diluted with 50 ml of ethyl acetate and 50 ml of water. The organic phase is then recovered, dried over sodium sulfate and filtered. 2 g of silica are then added to the filtrate before being concentrated under reduced pressure. The powder obtained is used as a solid deposit for chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (85/15). 0.534 g (71%) of the expected compound is recovered in the form of a yellow powder.
LC-MS: M + H = 287
1 H NMR (DMSO) δ (ppm): 2.48 (m, 3H); 7.00 (m, 2H); 7.32 (m, 2H); 7.88 (m, 2H); 8.00 (m, 1H); 8.68 (d, 1H).

10.4 N-méthyl-3-(4,4,5,5-tétraméthyl-[1,3,2]dioxaborolan-2-yl)benzamide10.4 N -methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzamide

2,50 g (11,68 mmol) de 3-bromo-N-méthylbenzamide, 3,56 g (14,01 mmol) de bis(pinacolato)dibore, 3,43 g (35,04 mmol) d'acétate de potassium et 0,953 g (1,17 mmol) de [1,1'-bis(diphénylphosphino)ferrocène]dichloropalladium (II) sont mis en présence de 20 mL de dioxanne avant d'être irradiés par onde micro-onde à 130 °C pendant 45 minutes. Le milieu est ensuite dilué avec 150 mL d'acétate d'éthyle et 100 mL d'eau. La phase organique est récupérée et la phase aqueuse est extraite avec 2 fois 100 mL d'acétate d'éthyle. Les phases organiques sont alors réunies, séchées sur sulfate de sodium puis concentrées sous pression réduite après avoir ajouté 10 g de silice. Le résidu obtenu est chromatographié sur gel de silice en éluant avec un mélange de cyclohexane et d'acétate d'éthyle (8/2).2.50 g (11.68 mmol) of 3-bromo- N- methylbenzamide, 3.56 g (14.01 mmol) of bis (pinacolato) diborone, 3.43 g (35.04 mmol) of potassium acetate and 0.953 g (1.17 mmol) of [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) are used. presence of 20 mL of dioxane before being irradiated by microwave at 130 ° C for 45 minutes. The medium is then diluted with 150 ml of ethyl acetate and 100 ml of water. The organic phase is recovered and the aqueous phase is extracted with 2 times 100 ml of ethyl acetate. The organic phases are then combined, dried over sodium sulfate and then concentrated under reduced pressure after adding 10 g of silica. The residue obtained is chromatographed on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (8/2).

On obtient 1,39 g de composé attendu sous forme d'une poudre rosée (présence de pinacol). RMN 1H (DMSO) δ (ppm): 1,30 (s, 12H) ; 2,78 (d, 3H) ; 7,48 (t, 1H) ; 7,80 (m, 1H) ; 7,95 (m, 1H) ; 8,12 (m, 1H) ; 8,50 (m, 1H).1.39 g of the expected compound are obtained in the form of a pink powder (presence of pinacol). 1 H NMR (DMSO) δ (ppm): 1.30 (s, 12H); 2.78 (d, 3H); 7.48 (t, 1H); 7.80 (m, 1H); 7.95 (m, 1H); 8.12 (m, 1H); 8.50 (m, 1H).

10.5 N-Méthyl-3-(2-p-tolylpyrazolo[1,5-a]pyridin-5-yl)benzamide10.5 N -Methyl-3- (2-p-tolylpyrazolo [1,5- a ] pyridin-5-yl) benzamide

On place 0,150g (0,52 mmol) de 5-bromo-2-p-tolylpyrazolo[1,5-a]pyridine obtenu à l'étape 13.3, 0,136 g (0,52 mmol) de N-méthyl-3-(4,4,5,5-tétraméthyl-[1,3,2]dioxaborolan-2-yl)benzamide obtenu à l'étape 13.4, 0,510 g (1,57 mmol) de carbonate de césium et 0,043 g (0,05 mmol) de [1,1'-bis(diphénylphosphino)ferrocène]dichloropalladium (II) dans 5 mL d'un mélange 9/1 de tétrahydrofurane et d'eau. Le milieu est agité à 65°C pendant 4 heures. Le milieu est ensuite dilué avec 50 mL de dichlorométhane et 50 mL d'eau. Le milieu biphasique est alors filtré sur cartouche hydrophobe (Colonne d'extraction liquide/liquide 70 mL, Radleys®). La phase organique est récupérée et concentrée sous pression réduite après avoir ajouté 1,5 g de silice. Le résidu obtenu est chromatographié sur gel de silice en éluant avec un mélange de cyclohexane et d'acétate d'éthyle (1/1).0.150 g (0.52 mmol) of 5-bromo-2-p-tolylpyrazolo [1,5- a ] pyridine obtained in step 13.3 are placed, 0.136 g (0.52 mmol) of N- methyl-3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzamide obtained in step 13.4, 0.510 g (1.57 mmol) of cesium carbonate and 0.043 g (0, 05 mmol) of [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) in 5 mL of a 9/1 mixture of tetrahydrofuran and water. The medium is stirred at 65 ° C. for 4 hours. The medium is then diluted with 50 ml of dichloromethane and 50 ml of water. The biphasic medium is then filtered on a hydrophobic cartridge (liquid / liquid extraction column 70 ml, Radleys®). The organic phase is recovered and concentrated under reduced pressure after adding 1.5 g of silica. The residue obtained is chromatographed on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1/1).

On obtient 0,138 g (77,7%) de composé attendu sous forme d'une poudre beige.
Point de fusion (°C) : 204-206
LC-MS : M+H = 342
RMN 1H (DMSO) δ (ppm): 2,38 (s, 3H) ; 2,85 (d, 3H) ; 7,10 (s, 1H) ; 7,31 (m, 3H) ; 7,62 (t, 1H) ; 7,90 (m, 3H) ; 7,98 (d, 1H) ; 8,08 (s, 1H) ; 8,29 (s, 1H) ; 8,61 (d, 1H) ; 8,81 (d, 1H).0.138 g (77.7%) of the expected compound is obtained in the form of a beige powder.
Melting point (° C): 204-206
LC-MS: M + H = 342
1 H NMR (DMSO) δ (ppm): 2.38 (s, 3H); 2.85 (d, 3H); 7.10 (s, 1H); 7.31 (m, 3H); 7.62 (t, 1H); 7.90 (m, 3H); 7.98 (d, 1H); 8.08 (s, 1H); 8.29 (s, 1H); 8.61 (d, 1H); 8.81 (d, 1H).

Exemple 11: 3-[3-Chloro-2-(4-fluorophényl)pyrazolo[1,5-a]pyridin-5-yl]-N-méthylbenzamide (exemple 34 du tableau) Example 11: 3- [3-Chloro-2- (4-fluorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] -N- methylbenzamide (Table Example 34)

0,100 g (0,29 mmol) de 3-[2-(4-fluorophényl)pyrazolo[1,5-a]pyridin-5-yl]-N méthylbenzamide obtenu selon le protocole 6 sont placés dans un ballon en présence de 3 mL de dichlorométhane. 0,060 g (0,45 mmol) de N-chlorosuccinimide sont ajoutés avant d'agiter le milieu à température ambiante pendant une nuit. Le milieu réactionnel est ensuite dilué avec 50 mL de dichlorométhane et 50 mL d'eau. On filtre alors le milieu biphasique sur cartouche hydrophobe (Colonne d'extraction liquide/liquide 70 mL, Radleys®). La phase organique est récupérée et concentrée sous pression réduite après avoir ajouté 1,2 g de silice. Le résidu obtenu est chromatographié sur gel de silice en éluant avec un mélange de cyclohexane et d'acétate d'éthyle (6/4).0.100 g (0.29 mmol) of 3- [2- (4-fluorophenyl) pyrazolo [1,5- a ] pyridin-5-yl] -N methylbenzamide obtained according to protocol 6 are placed in a flask in the presence of 3 mL of dichloromethane. 0.060 g (0.45 mmol) of N -chlorosuccinimide are added before stirring the medium at room temperature overnight. The reaction medium is then diluted with 50 mL of dichloromethane and 50 mL of water. The biphasic medium is then filtered on a hydrophobic cartridge (liquid / liquid extraction column 70 ml, Radleys®). The organic phase is recovered and concentrated under reduced pressure after adding 1.2 g of silica. The residue obtained is chromatographed on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (6/4).

On obtient 0,0592 g (53,8%) de composé attendu sous forme d'une poudre blanche.
Point de fusion (°C) : 221-223
LC-MS : M+H = 380
RMN-1H (DMSO) δ (ppm) : 2,88 (d, 3H) ; 7,42 (m, 2H) ; 7,47 (dd, 1H) ; 7,64 (t, 1H) ; 7,93 (m, 1H) ; 8,01 (m, 1H) ; 8,05 (m, 1H) ; 8,10 (m, 2H) ; 8,31 (m, 1H) ; 8,63 (m, 1H) ; 8,88 (d, 1H).0.0592 g (53.8%) of expected compound is obtained in the form of a white powder.
Melting point (° C): 221-223
LC-MS: M + H = 380
1 H NMR (DMSO) δ (ppm): 2.88 (d, 3H); 7.42 (m, 2H); 7.47 (dd, 1H); 7.64 (t, 1H); 7.93 (m, 1H); 8.01 (m, 1H); 8.05 (m, 1H); 8.10 (m, 2H); 8.31 (m, 1H); 8.63 (m, 1H); 8.88 (d, 1H).

Les tableaux qui suivent illustrent les structures chimiques de formule générale (I) (tableau 1) et les caractéristiques physicochimiques (tableau 2) de quelques exemples de composés selon l'invention.The following tables illustrate the chemical structures of general formula (I) (Table 1) and the physicochemical characteristics (Table 2) of some examples of compounds according to the invention.

Dans ces tableaux :

  • la colonne « PF » renseigne les points de fusion des produits en degrés Celsius (°C) ;
  • Me, Et représentent respectivement un groupe méthyle et éthyle ;
  • * indique le ou les atome(s) de liaison.
    Figure imgb0008
Tableau 1 No R1 Position (C=O)R1 X Y R 1 OMe 3 4-Cl H H 2 NH2 3 4-Cl H H 3 N(Me)2 3 4-Cl H H 4 NHMe 3 4-Cl H H 5 OMe 3 4-F H H 6 NHMe 3 4-F H H 7
Figure imgb0009
 3 4-F H H 8 N(Me)2 3 4-F H H 9
Figure imgb0010
 3 4-F H H 10 NHMe 3 4-F 2-Me H 11 NHMe 3 4-F 4-Cl H 12 NHMe 3 4-F 6-Cl H 13 NHMe 3 4-F 6-Me H 14 NHMe 4 4-F 3-F H 15
Figure imgb0011
 3 4-F H H 16
Figure imgb0012
 3 4-F H H 17 NHMe 3 2,6-diF H H 18 NHMe 3 2-F H H 19 NHMe 3 4-CF3 H H 20 NHMe 4 4-F H H 21 NHMe 2 4-F H H 22
Figure imgb0013
 3 4-F H H 23 NHMe 3 2,4-diF H H 24 NHMe 3 4-OCF3 H H 25 NHMe 3 3,4-diF H H 26 NHMe 3 3,5-diF H H 27 NHMe 3 3-F H H 28 NHMe 3 4-Me H H 29 NHMe 3 4-OMe H H 30 NHMe 3 3,4-diMe H H 31 NHMe 3 4-CN H H 32 NHMe 3 2,3-diF H H 33 NHMe 3 2-Me H H 34 NHMe 3 4-F H Cl Tableau 2 No PF °C RMN / [M+H] 1 180-182 RMN-1H (DMSO) δ (ppm) : 3,95 (s, 3H) ; 7,20 (s, 1H) ; 7,35 (d, 1H) ; 7,60 (d, 2H) ; 7,70 (t, 1H) ; de 8,00 à 8,20 (m, 5H) ; 8,35 (s, 1H) ; 8,85 (d, 1H). M+H = 363 2 283-285 RMN-1H (DMSO) δ (ppm) : 7,17 (s, 1H) ; 7,36 (dd, 1H) ; 7,47 (s, 1H) ; 7,56 (m, 2H) ; 7,61 (t, 1H) ; 7,94 (m, 1H) ; 8,00 (m, 1H) ; 8,07 (m, 2H) ; 8,11 (m, 1H) ; 8,15 (s, 1H) ; 8,32 (m, 1H) ; 8,82 (d, 1H). M+H = 348 3 175-177 RMN-1H (DMSO) δ (ppm) : 3,02 (d, 6H) ; 7,15 (s, 1H) ; 7,35 (dd, 1H) ; 7,46 (m, 1H) ; de 7,50 à 7,67 (m, 3H) ; 7,85 (m, 1H) ; 7,91 (m, 1H) ; de 8,00 à 8,15 (m, 3H) ; 8,80 (d, 1H). M+H = 376 4 234-236 RMN-1H (DMSO) δ (ppm) : 2,85 (d, 3H) ; 7,18 (s, 1H) ; 7,35 (m, 1H) ; de 7,51 à 7,68 (m, 3H) ; 7,90 (m, 1H) ; 8,00 (m, 1H) ; de 8,02 à 8,12 (m, 3H) ; 8,28 (m, 1H) ; 8,62 (m, 1H) ; 8,82 (d, 1H). M+H = 362 5 162-164 RMN-1H (DMSO) δ (ppm) : 3,95 (s, 3H) ; 7,15 (s, 1H) ; de 7,30 à 7,38 (m, 3H) ; 7,70 (t, 1H) ; de 8,00 à 8,15 (m, 5H) ; 8,35 (m, 1H) ; 8,80 (d, 1 H). M+H = 347 6 214-216 RMN-1H (DMSO) δ (ppm) : 2,85 (d, 3H) ; 7,15 (s, 1H) ; de 7,26 à 7,46 (m, 3H) ; 7,62 (m, 1H) ; 7,90 (m, 1H) ; 8,00 (m, 1H) ; de 8,05 à 8,21 (m, 3H) ; 8,29 (m, 1H) ; 8,60 (m, 1H) ; 8,82 (d, 1H). M+H = 346 7 210-212 RMN 1H (DMSO) δ (ppm): 1,23 (d, 6H) ; 4,18 (m, 1H) ; 7,14 (s, 1H) ; 7,34 (m, 3H) ; 7,62 (t, 1H) ; 7,90 (d, 1H) ; 7,99 (d, 1H) ; 8,07 (m, 3H) ; 8,24 (s, 1H) ; 8,47 (d, 1H) ; 8,80 (d, 1H). M+H=374. 8 131-133 RMN 1H (DMSO) δ (ppm): 3,03 (d, 6H) ; 7,12 (s, 1H) ; de 7,30 à 7,39 (m, 3H) ; 7,47 (d, 1H) ; 7,57 (t, 1H) ; 7,82 (s, 1H) ; 7,90 (d, 1H) ; 8,07 (m, 3H) ; 8,78 (d, 1H).M+H=360. 9 152-154 RMN 1H (DMSO) δ (ppm): de 3,38 à 3,80 (m, 8H) ; 7,13 (s, 1H) ; 7,30 à 7,39 (m, 3H) ; 7,47 (d, 1H) ; 7,62 (t, 1H) ; 7,85 (s, 1H) ; 7,95 (d, 1H) ; 8,08 (m, 3H) ; 8,80 (d, 1H). M+H=402. 10 240-242 RMN 1H (DMSO) δ (ppm): 2,37 (s, 3H) ; 2,80 (d, 3H) ; 6,86 (d, 1H) ; 7,10 (s, 1H) ; de 7,33 à 7,44 (m, 5H) ; 7,63 (s, 1H) ; 8,10 (m, 2H) ; 8,28 (s, 1H) ; 8,76 (d, 1H). M+H=360. 11 243-245 RMN 1H (DMSO) δ (ppm): 2,83 (d, 3H) ; 7,12 (s, 1H) ; de 7,27 à 7,35 (m, 3H) ; 7,62 (d, 1H) ; 7,90 (m, 2H) ; de 8,04 à 8,16 (m, 3H) ; 8,46 (s, 1H) ; 8,80 (d, 1H). M+H=380. 12 188-190 RMN 1H (DMSO) δ (ppm): 2,83 (d, 3H) ; 7,05 (d, 1H) ; 7,18 (s, 1H) ; 7,35 (m, 2H) ; 7,74 (d, 1H) ; 7,83 (s, 1H) ; 7,90 (d, 1H) ; 8,01 (s, 1H) ; 8,10 (m, 2H) ; 8,61 (s, 1H) ; 8,82 (d, 1H). M+H=380. 13 185-187 RMN 1H (DMSO) δ (ppm): 2,49 (s, 3H) ; 2,83 (d, 3H) ; 6,97 (d, 1H) ; 7,10 (s, 1H) ; 7,35 (m, 2H) ; 7,46 (d, 1H) ; 7,70 (s, 1H) ; 7,83 (m, 2H) ; 8,08 (m, 2H) ; 8,47 (s, 1H) ; 8,77 (d, 1H). M+H=360. 14 227-229 RMN 1H (DMSO) δ (ppm): 2,83 (d, 3H) ; 7,14 (s, 1H) ; de 7,30 à 7,39 (m, 3H) ; de 7,74 à 7,85 (m, 3H) ; 8,08 (m, 2H) ; 8,18 (s, 1H) ; 8,39 (s, 1H) ; 8,80 (d, 1H). M+H=364. 15 179-181 RMN 1H (DMSO) δ (ppm): de 0,60 à 0,80 (m, 4H) ; 3,92 (m, 1H) ; 7,15 (s, 1H) ; de 7,30 à 7,39 (m, 3H) ; 7,61 (t, 1H) ; 7,88 (d, 1H) ; 7,98 (d, 1H) ; 8,10 (m, 3H) ; 8,22 (s, 1H) ; 8,57 (m, 1H) ; 8,81 (d, 1H). M+H=372. 16 164-166 RMN 1H (DMSO) δ (ppm): de 1,80 à 2,00 (m, 4H) ; de 3,43 à 3,56 (m, 4H) ; 7,12 (s, 1H) ; 7,30 à 7,39 (m, 3H) ; de 7,55 à 7,63 (m, 2H) ; 7,95 (m, 2H) ; 8,07 (m, 3H) ; 8,75 (d, 1H). M+H=386. 17 207-209 RMN 1H (DMSO) δ (ppm): 2,85 (d, 3H) ; 7,00 (s, 1H) ; de 7,25 à 7,35 (m, 2H) ; 7,41 (d, 1H) ; de 7,54 à 7,68 (m, 2H) ; 7,93 (d, 1H) ; 8,00 (d, 1H) ; 8,17 (s, 1H) ; 8,28 (s, 1H) ; 8,60 (m, 1H) ; 8,92 (d, 1H). M+H=364. 18 195-197 RMN 1H (DMSO) δ (ppm): 2,85 (d, 3H) ; 7,10 (s, 1H) ; de 7,32 à 7,43 (m, 3H) ; 7,48 (m, 1H) ; 7,65 (t, 1H) ; 7,91 (d, 1H) ; 7,99 (d, 1H) ; 8,18 (m, 2H) ; 8,28 (s, 1H) ; 8,60 (m, 1H) ; 8,87 (d, 1H). M+H=346. 19 220-222 RMN 1H (DMSO) δ (ppm): 2,82 (d, 3H) ; 7,30 (s, 1H) ; 7,39 (d, 1H) ; 7,64 (t, 1H) ; de 7,84 à 7,95 (m, 3H); 8,00 (d, 1H) ; 8,13 (s, 1H) ; 8,27 (m, 3H) ; 8,60 (m, 1H) ; 8,85 (d, 1H). M+H=396. 20 264-266 RMN 1H (DMSO) δ (ppm): 2,65 (d, 3H) ; 6,86 (d, 1H) ; 7,14 (s, 1H) ; 7,34 (m, 2H) ; de 7,48 à 7,59 (m, 4H) ; 7,66 (s, 1H) ; 8,09 (m, 2H) ; 8,23 (d, 1H) ; 8,72 (d, 1H). M+H=346. 21 208-210 RMN 1H (DMSO) δ (ppm): 2,84 (d, 3H) ; 7,14 (s, 1H) ; 7,34 (m, 3H) ; 7,95 (m, 4H) ; 8,09 (m, 3H) ; 8,55 (d, 1H) ; 8,80 (d, 1H). M+H=346. 22 173-175 RMN 1H (DMSO) δ (ppm): de 1,65 à 2,05 (m, 2H) ; de 3,40 à 3,70 (m, 4H) ; 4,32 (d, 1h) ; 5,00 (d, 1H) ; 7,11 (s, 1H) ; 7,32 (m, 3H) ; 7,60 (m, 2H) ; 7,93 (d, 2H) ; 8,08 (m, 3H) ; 8,77 (d, 1H). M+H=402. 23 210-212 RMN 1H (DMSO) δ (ppm): 2,87 (d, 3H) ; 7,07 (s, 1H) ; 7,25 (t, 1H) ; de 7,38 à 7,48 (m, 2H) ; 7,63 (t, 1H) ; 7,91 (d, 1H) ; 7,98 (d, 1H) ; 8,18 (m, 2H) ; 8,28 (s, 1H) ; 8,60 (m, 1H) ; 8,87 (d, 1H). M+H=364. 24 212-214 RMN 1H (DMSO) δ (ppm): 2,85 (d, 3H) ; 7,21 (s, 1H) ; 7,36 (d, 1H) ; 7,50 (d, 2H) ; 7,62 (t, 1H) ; 7,90 (d, 1H) ; 8,00 (d, 1H); 8,12 (s, 1H) ; 8,18 (d, 2H) ; 8,27 (s, 1H) ; 8,60 (d, 1H) ; 8,83 (d, 1H). MP=211°C. M+H=412. 25 209-211 RMN 1H (DMSO) δ (ppm): 2,87 (d, 3H) ; 7,21 (s, 1H) ; 7,39 (d, 1H) ; de 7,54 à 7,68 (m, 2H) ; 7,90 (d, 2H) ; 8,00 (d, 1H) ; de 8,04 à 8,13 (m, 2H) ; 8,27 (s, 1H) ; 8,60 (d, 1H) ; 8,83 (d, 1H). M+H=364. 26 230-232 RMN 1H (DMSO) δ (ppm): 2,85 (d, 3H) ; 7,30 (m, 2H) ; 7,39 (d, 1H) ; 7,63 (t, 1H) ; 7,78 (m, 2H) ; 7,92 (d, 1H) ; 8,01 (d, 1H); 8,13 (s, 1H) ; 8,27 (s, 1H) ; 8,61 (d, 1H) ; 8,84 (d, 1H). M+H=364. 27 204-206 RMN 1H (DMSO) δ (ppm): 2,85 (d, 3H) ; 7,26 (m, 2H) ; 7,37 (d, 1H) ; de 7,53 à 7,64 (m, 2H) ; 7,82 (d, 1H) ; 7,90 (d, 2H) ; 8,00 (d, 1H) ; 8,11 (s, 1H) ; 8,27 (s, 1H) ; 8,61 (d, 1H) ; 8,85 (d, 1H). M+H=346. 28 204-206 RMN 1H (DMSO) δ (ppm): 2,38 (s, 3H) ; 2,85 (d, 3H) ; 7,10 (s, 1H) ; 7,31 (m, 3H) ; 7,62 (t, 1H) ; 7,90 (m, 3H) ; 7,98 (d, 1H) ; 8,08 (s, 1H) ; 8,29 (s, 1H) ; 8,61 (d, 1H) ; 8,81 (d, 1H). M+H=342. 29 211-213 RMN 1H (DMSO) δ (ppm): 2,85 (d, 3H) ; 3,82 (s, 3H) ; 7,06 (d, 3H) ; 7,31 (d, 1H) ; 7,64 (t, 1H) ; 7,90 (d, 1H) ; 7,98 (m, 3H) ; 8,07 (s, 1H) ; 8,27 (s, 1H) ; 8,61 (d, 1H) ; 8,80 (d, 1H). M+H=358. 30 187-189 RMN 1H (DMSO) δ (ppm): 2,28 (s, 3H) ; 2,32 (s, 3H) ; 2,86 (d, 3H) ; 7,10 (s, 1H) ; 7,28 (d, 1H) ; 7,31 (d, 1H) ; 7,64 (t, 1H) ; 7,75 (d, 1H) ; 7,81 (s, 1H) ; 7,90 (d, 1H) ; 7,99 (d, 1H) ; 8,07 (s, 1H) ; 8,26 (s, 1H) ; 8,62 (d, 1H) ; 8,80 (d, 1H). M+H=356. 31 252-254 RMN 1H (DMSO) δ (ppm): 2,87 (d, 3H) ; 7,32 (s, 1H) ; 7,43 (d, 1H) ; 7,63 (t, 1H) ; 7,92 (d, 1H) ; 8,00 (m, 3H) ; 8,15 (s, 1H) ; 8,27 (m, 3H) ; 8,62 (d, 1H) ; 8,87 (d, 1H). M+H=353. 32 214-216 RMN 1H (DMSO) δ (ppm): 2,85 (d, 3H) ; 7,13 (s, 1H) ; de 7,32 à 7,43 (m, 2H) ; 7,50 (m, 1H) ; 7,63 (t, 1H) ; 7,90 (d, 1H) ; 7,97 (m, 2H) ; 8,17 (s, 1H) ; 8,27 (s, 1H) ; 8,60 (d, 1H) ; 8,88 (d, 1H). M+H=364. 33 129-131 RMN 1H (DMSO) δ (ppm): 2,55 (s, 3H) ; 2,85 (d, 3H) ; 6,93 (s, 1H) ; 7,35 (m, 4H) ; 7,63 (t, 1H) ; 7,72 (m, 1H) ; 7,90 (d, 1H) ; 8,00 (d, 1H) ; 8,10 (s, 1H) ; 8,27 (s, 1H) ; 8,61 (d, 1H) ; 8,83 (d, 1H). M+H=342. 34 221-223 RMN-1H (DMSO) δ (ppm) : 2,88 (d, 3H) ; 7,42 (m, 2H) ; 7,47 (dd, 1H) ; 7,64 (t, 1H) ; 7,93 (m, 1H) ; 8,01 (m, 1H) ; 8,05 (m, 1H) ; 8,10 (m, 2H) ; 8,31 (m, 1H) ; 8,63 (m, 1H) ; 8,88 (d, 1H). M+H = 380 In these paintings:
  • the column "PF" gives the product melting points in degrees Celsius (° C);
  • Me, Et respectively represent a methyl and ethyl group;
  • * indicates the bond atom (s).
    Figure imgb0008
<b><u> Table 1 </ u></b> No. R1 Position (C = O) R1 X Y R 1 OMe 3 4-Cl H H 2 NH 2 3 4-Cl H H 3 N (Me) 2 3 4-Cl H H 4 NHMe 3 4-Cl H H 5 OMe 3 4-F H H 6 NHMe 3 4-F H H 7
Figure imgb0009
 3 4-F H H 8 N (Me) 2 3 4-F H H 9
Figure imgb0010
 3 4-F H H 10 NHMe 3 4-F 2-Me H 11 NHMe 3 4-F 4-Cl H 12 NHMe 3 4-F 6-Cl H 13 NHMe 3 4-F 6-Me H 14 NHMe 4 4-F 3-F H 15
Figure imgb0011
 3 4-F H H 16
Figure imgb0012
 3 4-F H H 17 NHMe 3 2,6-diF H H 18 NHMe 3 2 F H H 19 NHMe 3 4-CF 3 H H 20 NHMe 4 4-F H H 21 NHMe 2 4-F H H 22
Figure imgb0013
 3 4-F H H 23 NHMe 3 2,4-diF H H 24 NHMe 3 4-OCF 3 H H 25 NHMe 3 3,4-diF H H 26 NHMe 3 3,5-diF H H 27 NHMe 3 3-F H H 28 NHMe 3 4-Me H H 29 NHMe 3 4-OMe H H 30 NHMe 3 3.4 -diMe H H 31 NHMe 3 4-CN H H 32 NHMe 3 2,3-diF H H 33 NHMe 3 2-Me H H 34 NHMe 3 4-F H Cl No. PF ° C NMR / [M + H] 1 180-182 1 H NMR (DMSO) δ (ppm): 3.95 (s, 3H); 7.20 (s, 1H); 7.35 (d, 1H); 7.60 (d, 2H); 7.70 (t, 1H); from 8.00 to 8.20 (m, 5H); 8.35 (s, 1H); 8.85 (d, 1H). M + H = 363 2 283-285 1 H NMR (DMSO) δ (ppm): 7.17 (s, 1H); 7.36 (dd, 1H); 7.47 (s, 1H); 7.56 (m, 2H); 7.61 (t, 1H); 7.94 (m, 1H); 8.00 (m, 1H); 8.07 (m, 2H); 8.11 (m, 1H); 8.15 (s, 1H); 8.32 (m, 1H); 8.82 (d, 1H). M + H = 348 3 175-177 1 H NMR (DMSO) δ (ppm): 3.02 (d, 6H); 7.15 (s, 1H); 7.35 (dd, 1H); 7.46 (m, 1H); from 7.50 to 7.67 (m, 3H); 7.85 (m, 1H); 7.91 (m, 1H); from 8.00 to 8.15 (m, 3H); 8.80 (d, 1H). M + H = 376 4 234-236 1 H NMR (DMSO) δ (ppm): 2.85 (d, 3H); 7.18 (s, 1H); 7.35 (m, 1H); from 7.51 to 7.68 (m, 3H); 7.90 (m, 1H); 8.00 (m, 1H); from 8.02 to 8.12 (m, 3H); 8.28 (m, 1H); 8.62 (m, 1H); 8.82 (d, 1H). M + H = 362 5 162-164 1 H NMR (DMSO) δ (ppm): 3.95 (s, 3H); 7.15 (s, 1H); from 7.30 to 7.38 (m, 3H); 7.70 (t, 1H); from 8.00 to 8.15 (m, 5H); 8.35 (m, 1H); 8.80 (d, 1H). M + H = 347 6 214-216 1 H NMR (DMSO) δ (ppm): 2.85 (d, 3H); 7.15 (s, 1H); from 7.26 to 7.46 (m, 3H); 7.62 (m, 1H); 7.90 (m, 1H); 8.00 (m, 1H); from 8.05 to 8.21 (m, 3H); 8.29 (m, 1H); 8.60 (m, 1H); 8.82 (d, 1H). M + H = 346 7 210-212 1 H NMR (DMSO) δ (ppm): 1.23 (d, 6H); 4.18 (m, 1H); 7.14 (s, 1H); 7.34 (m, 3H); 7.62 (t, 1H); 7.90 (d, 1H); 7.99 (d, 1H); 8.07 (m, 3H); 8.24 (s, 1H); 8.47 (d, 1H); 8.80 (d, 1H). M + H = 374. 8 131-133 1 H NMR (DMSO) δ (ppm): 3.03 (d, 6H); 7.12 (s, 1H); from 7.30 to 7.39 (m, 3H); 7.47 (d, 1H); 7.57 (t, 1H); 7.82 (s, 1H); 7.90 (d, 1H); 8.07 (m, 3H); 8.78 (d, 1H) .M + H = 360. 9 152-154 1 H NMR (DMSO) δ (ppm): from 3.38 to 3.80 (m, 8H); 7.13 (s, 1H); 7.30-7.39 (m, 3H); 7.47 (d, 1H); 7.62 (t, 1H); 7.85 (s, 1H); 7.95 (d, 1H); 8.08 (m, 3H); 8.80 (d, 1H). M + H = 402. 10 240-242 1 H NMR (DMSO) δ (ppm): 2.37 (s, 3H); 2.80 (d, 3H); 6.86 (d, 1H); 7.10 (s, 1H); from 7.33 to 7.44 (m, 5H); 7.63 (s, 1H); 8.10 (m, 2H); 8.28 (s, 1H); 8.76 (d, 1H). M + H = 360. 11 243-245 1 H NMR (DMSO) δ (ppm): 2.83 (d, 3H); 7.12 (s, 1H); from 7.27 to 7.35 (m, 3H); 7.62 (d, 1H); 7.90 (m, 2H); from 8.04 to 8.16 (m, 3H); 8.46 (s, 1H); 8.80 (d, 1H). M + H = 380. 12 188-190 1 H NMR (DMSO) δ (ppm): 2.83 (d, 3H); 7.05 (d, 1H); 7.18 (s, 1H); 7.35 (m, 2H); 7.74 (d, 1H); 7.83 (s, 1H); 7.90 (d, 1H); 8.01 (s, 1H); 8.10 (m, 2H); 8.61 (s, 1H); 8.82 (d, 1H). M + H = 380. 13 185-187 1 H NMR (DMSO) δ (ppm): 2.49 (s, 3H); 2.83 (d, 3H); 6.97 (d, 1H); 7.10 (s, 1H); 7.35 (m, 2H); 7.46 (d, 1H); 7.70 (s, 1H); 7.83 (m, 2H); 8.08 (m, 2H); 8.47 (s, 1H); 8.77 (d, 1H). M + H = 360. 14 227-229 1 H NMR (DMSO) δ (ppm): 2.83 (d, 3H); 7.14 (s, 1H); from 7.30 to 7.39 (m, 3H); from 7.74 to 7.85 (m, 3H); 8.08 (m, 2H); 8.18 (s, 1H); 8.39 (s, 1H); 8.80 (d, 1H). M + H = 364. 15 179-181 1 H NMR (DMSO) δ (ppm): 0.60 to 0.80 (m, 4H); 3.92 (m, 1H); 7.15 (s, 1H); from 7.30 to 7.39 (m, 3H); 7.61 (t, 1H); 7.88 (d, 1H); 7.98 (d, 1H); 8.10 (m, 3H); 8.22 (s, 1H); 8.57 (m, 1H); 8.81 (d, 1H). M + H = 372. 16 164-166 1 H NMR (DMSO) δ (ppm): from 1.80 to 2.00 (m, 4H); from 3.43 to 3.56 (m, 4H); 7.12 (s, 1H); 7.30-7.39 (m, 3H); 7.55 to 7.63 (m, 2H); 7.95 (m, 2H); 8.07 (m, 3H); 8.75 (d, 1H). M + H = 386. 17 207-209 1 H NMR (DMSO) δ (ppm): 2.85 (d, 3H); 7.00 (s, 1H); from 7.25 to 7.35 (m, 2H); 7.41 (d, 1H); from 7.54 to 7.68 (m, 2H); 7.93 (d, 1H); 8.00 (d, 1H); 8.17 (s, 1H); 8.28 (s, 1H); 8.60 (m, 1H); 8.92 (d, 1H). M + H = 364. 18 195-197 1 H NMR (DMSO) δ (ppm): 2.85 (d, 3H); 7.10 (s, 1H); from 7.32 to 7.43 (m, 3H); 7.48 (m, 1H); 7.65 (t, 1H); 7.91 (d, 1H); 7.99 (d, 1H); 8.18 (m, 2H); 8.28 (s, 1H); 8.60 (m, 1H); 8.87 (d, 1H). M + H = 346. 19 220-222 1 H NMR (DMSO) δ (ppm): 2.82 (d, 3H); 7.30 (s, 1H); 7.39 (d, 1H); 7.64 (t, 1H); from 7.84 to 7.95 (m, 3H); 8.00 (d, 1H); 8.13 (s, 1H); 8.27 (m, 3H); 8.60 (m, 1H); 8.85 (d, 1H). M + H = 396. 20 264-266 1 H NMR (DMSO) δ (ppm): 2.65 (d, 3H); 6.86 (d, 1H); 7.14 (s, 1H); 7.34 (m, 2H); from 7.48 to 7.59 (m, 4H); 7.66 (s, 1H); 8.09 (m, 2H); 8.23 (d, 1H); 8.72 (d, 1H). M + H = 346. 21 208-210 1 H NMR (DMSO) δ (ppm): 2.84 (d, 3H); 7.14 (s, 1H); 7.34 (m, 3H); 7.95 (m, 4H); 8.09 (m, 3H); 8.55 (d, 1H); 8.80 (d, 1H). M + H = 346. 22 173-175 1 H NMR (DMSO) δ (ppm): from 1.65 to 2.05 (m, 2H); from 3.40 to 3.70 (m, 4H); 4.32 (d, 1h); 5.00 (d, 1H); 7.11 (s, 1H); 7.32 (m, 3H); 7.60 (m, 2H); 7.93 (d, 2H); 8.08 (m, 3H); 8.77 (d, 1H). M + H = 402. 23 210-212 1 H NMR (DMSO) δ (ppm): 2.87 (d, 3H); 7.07 (s, 1H); 7.25 (t, 1H); from 7.38 to 7.48 (m, 2H); 7.63 (t, 1H); 7.91 (d, 1H); 7.98 (d, 1H); 8.18 (m, 2H); 8.28 (s, 1H); 8.60 (m, 1H); 8.87 (d, 1H). M + H = 364. 24 212-214 1 H NMR (DMSO) δ (ppm): 2.85 (d, 3H); 7.21 (s, 1H); 7.36 (d, 1H); 7.50 (d, 2H); 7.62 (t, 1H); 7.90 (d, 1H); 8.00 (d, 1H); 8.12 (s, 1H); 8.18 (d, 2H); 8.27 (s, 1H); 8.60 (d, 1H); 8.83 (d, 1H). MP = 211 ° C. M + H = 412. 25 209-211 1 H NMR (DMSO) δ (ppm): 2.87 (d, 3H); 7.21 (s, 1H); 7.39 (d, 1H); from 7.54 to 7.68 (m, 2H); 7.90 (d, 2H); 8.00 (d, 1H); from 8.04 to 8.13 (m, 2H); 8.27 (s, 1H); 8.60 (d, 1H); 8.83 (d, 1H). M + H = 364. 26 230-232 1 H NMR (DMSO) δ (ppm): 2.85 (d, 3H); 7.30 (m, 2H); 7.39 (d, 1H); 7.63 (t, 1H); 7.78 (m, 2H); 7.92 (d, 1H); 8.01 (d, 1H); 8.13 (s, 1H); 8.27 (s, 1H); 8.61 (d, 1H); 8.84 (d, 1H). M + H = 364. 27 204-206 1 H NMR (DMSO) δ (ppm): 2.85 (d, 3H); 7.26 (m, 2H); 7.37 (d, 1H); from 7.53 to 7.64 (m, 2H); 7.82 (d, 1H); 7.90 (d, 2H); 8.00 (d, 1H); 8.11 (s, 1H); 8.27 (s, 1H); 8.61 (d, 1H); 8.85 (d, 1H). M + H = 346. 28 204-206 1 H NMR (DMSO) δ (ppm): 2.38 (s, 3H); 2.85 (d, 3H); 7.10 (s, 1H); 7.31 (m, 3H); 7.62 (t, 1H); 7.90 (m, 3H); 7.98 (d, 1H); 8.08 (s, 1H); 8.29 (s, 1H); 8.61 (d, 1H); 8.81 (d, 1H). M + H = 342. 29 211-213 1 H NMR (DMSO) δ (ppm): 2.85 (d, 3H); 3.82 (s, 3H); 7.06 (d, 3H); 7.31 (d, 1H); 7.64 (t, 1H); 7.90 (d, 1H); 7.98 (m, 3H); 8.07 (s, 1H); 8.27 (s, 1H); 8.61 (d, 1H); 8.80 (d, 1H). M + H = 358. 30 187-189 1 H NMR (DMSO) δ (ppm): 2.28 (s, 3H); 2.32 (s, 3H); 2.86 (d, 3H); 7.10 (s, 1H); 7.28 (d, 1H); 7.31 (d, 1H); 7.64 (t, 1H); 7.75 (d, 1H); 7.81 (s, 1H); 7.90 (d, 1H); 7.99 (d, 1H); 8.07 (s, 1H); 8.26 (s, 1H); 8.62 (d, 1H); 8.80 (d, 1H). M + H = 356. 31 252-254 1 H NMR (DMSO) δ (ppm): 2.87 (d, 3H); 7.32 (s, 1H); 7.43 (d, 1H); 7.63 (t, 1H); 7.92 (d, 1H); 8.00 (m, 3H); 8.15 (s, 1H); 8.27 (m, 3H); 8.62 (d, 1H); 8.87 (d, 1H). M + H = 353. 32 214-216 1 H NMR (DMSO) δ (ppm): 2.85 (d, 3H); 7.13 (s, 1H); from 7.32 to 7.43 (m, 2H); 7.50 (m, 1H); 7.63 (t, 1H); 7.90 (d, 1H); 7.97 (m, 2H); 8.17 (s, 1H); 8.27 (s, 1H); 8.60 (d, 1H); 8.88 (d, 1H). M + H = 364. 33 129-131 1 H NMR (DMSO) δ (ppm): 2.55 (s, 3H); 2.85 (d, 3H); 6.93 (s, 1H); 7.35 (m, 4H); 7.63 (t, 1H); 7.72 (m, 1H); 7.90 (d, 1H); 8.00 (d, 1H); 8.10 (s, 1H); 8.27 (s, 1H); 8.61 (d, 1H); 8.83 (d, 1H). M + H = 342. 34 221-223 1 H NMR (DMSO) δ (ppm): 2.88 (d, 3H); 7.42 (m, 2H); 7.47 (dd, 1H); 7.64 (t, 1H); 7.93 (m, 1H); 8.01 (m, 1H); 8.05 (m, 1H); 8.10 (m, 2H); 8.31 (m, 1H); 8.63 (m, 1H); 8.88 (d, 1H). M + H = 380

Les composés selon l'invention ont fait l'objet d'essais pharmacologiques permettant de déterminer leur effet modulateur sur NOT.The compounds according to the invention have been the subject of pharmacological tests for determining their modulatory effect on NOT.

Evaluation de l'activité in vitro sur cellules N2AEvaluation of in vitro activity on N2A cells

L'activité des composés selon l'invention a été évaluée sur une lignée cellulaire (N2A) exprimant de manière endogène le récepteur de souris Nurr1 et transfectée de manière stable avec l'élément de réponse liant NOT (NBRE) couplé au gène rapporteur luciférase. Les essais ont été réalisés selon le mode opératoire décrit ci dessous.The activity of the compounds according to the invention was evaluated on a cell line (N2A) endogenously expressing the Nurr1 mouse receptor and stably transfected with the NOT binding response element (NBRE) coupled to the luciferase reporter gene. The tests were carried out according to the procedure described below.

La lignée cellulaire Neuro-2A provient de source commerciale standard (ATCC). Le clone Neuro-2A a été obtenu à partir d'une tumeur spontanée provenant d'une souche de souris A albino par R.J Klebe et col. Cette lignée Neuro-2A est ensuite stablement transfectée avec 8NBRE-luciférase. Les cellules N2A-8NBRE sont cultivées jusqu'à confluence dans des flacons de culture de 75 cm2 contenant du DMEM supplémenté par 10% de sérum foetal de veau, 4,5 g/L de glucose et 0,4 mg/ml de Généticine. Après une semaine de culture, les cellules sont récupérées par de la trypsine 0,25% pendant 30 secondes puis remises en suspension dans du DMEM sans rouge de phénol contenant 4,5g/L de glucose, 10% de sérum délipidé Hyclone et déposées dans des plaques blanches 96 puits à fond transparent. Les cellules sont déposées à raison de 60.000 par puits dans 75 µL pendant 24 heures avant l'addition des produits. Les produits sont appliqués dans 25µL et incubés 24 heures supplémentaires. Le jour de la mesure, on ajoute à chaque puits un volume équivalent (100µL) de Steadylite, puis on attend 30 minutes pour obtenir une lyse complète des cellules et la production maximale du signal. Les plaques sont ensuite mesurées dans un compteur de luminescence pour microplaques après avoir été scellées par un film adhésif. Les produits sont préparés sous forme de solution stock à 10-2 M, puis dilués dans 100% de DMSO. Chaque concentration de produit est préalablement diluée dans du milieu de culture avant incubation avec les cellules contenant ainsi 0,625% final de DMSO.The Neuro-2A cell line comes from a standard commercial source (ATCC). The Neuro-2A clone was obtained from a spontaneous tumor from an albino mouse A strain by RJ Klebe et al. This Neuro-2A line is then stably transfected with 8NBRE-luciferase. The N2A-8NBRE cells are cultured to confluence in 75 cm 2 culture flasks containing DMEM supplemented with 10% fetal calf serum, 4.5 g / l glucose and 0.4 mg / ml Geneticin. . After one week of culture, the cells are recovered with 0.25% trypsin for 30 seconds and then resuspended in DMEM without phenol red containing 4.5 g / l of glucose, 10% of delipidated serum Hyclone and deposited in 96-well white plates with transparent bottom. The cells are deposited at a rate of 60,000 per well in 75 μL for 24 hours before the addition of the products. The products are applied in 25 μl and incubated for a further 24 hours. On the day of the measurement, an equivalent volume (100 μL) of Steadylite is added to each well, then waited for 30 minutes to obtain a complete lysis of the cells and the maximum production of the signal. The plates are then measured in a microplate luminescence counter after being sealed with an adhesive film. The products are prepared as a stock solution at 10 -2 M, then diluted in 100% DMSO. Each product concentration is previously diluted in culture medium before incubation with the cells thus containing 0.625% final DMSO.

Les meilleurs composés ont une CE50 comprise entre 0,1 nM et 10 µM.The best compounds have an EC50 of between 0.1 nM and 10 μM.

Par exemple, les composés n°2, 4, 10, 14, 16 et 26 ont montré une CE50 de 45 ; 2 ; 6,6 ; 125 ; 326 et 1,3 nM respectivement.For example, Compounds Nos. 2, 4, 10, 14, 16 and 26 showed an EC50 of 45; 2; 6.6; 125; 326 and 1.3 nM respectively.

Il apparaît donc que les composés selon l'invention ont un effet modulateur de NOT.It therefore appears that the compounds according to the invention have a modulating effect of NOT.

Les composés selon l'invention peuvent donc être utilisés pour la préparation de médicaments pour leur application en thérapeutique dans le traitement ou la prévention de maladies impliquant les récepteurs NOT.The compounds according to the invention can therefore be used for the preparation of medicaments for their therapeutic application in the treatment or prevention of diseases involving NOT receptors.

Ainsi, selon un autre de ses aspects, l'invention a pour objet des médicaments qui comprennent un composé de formule (I), ou un sel d'addition de ce dernier à un acide pharmaceutiquement acceptable.Thus, according to another of its aspects, the subject of the invention is medicaments which comprise a compound of formula (I), or an acid addition salt thereof. pharmaceutically acceptable.

Ces médicaments trouvent leur emploi en thérapeutique, notamment dans le traitement et la prévention des maladies neurodégénératives telles que par exemple la maladie de Parkinson, d'Alzheimer, les tauopathies (ex. la paralysie progressive supranucléaire, la démence fronto-temporale, la dégénérescence corticobasale, la maladie de Pick); les traumatismes cérébraux comme l'ischémie et les traumatismes crâniens et l'épilepsie ; les maladies psychiatriques comme la schizophrénie, la dépression, la dépendance à une substance, les troubles du déficit de l'attention et de l'hyperactivité ; les maladies inflammatoires du système nerveux central comme la sclérose en plaque, encéphalite, myélite et encéphalomyélite et autres maladies inflammatoires comme les pathologies vasculaires, l'athérosclérose, les inflammations des articulations, l'arthrose, l'arthrite rhumatoïde ; l'ostéoarthrite, la maladie de Crohn, colite ulcéreuse; les maladies inflammatoires allergiques telle que l'asthme, les maladies auto-immunes comme le diabète de type 1, lupus, sclérodermies, Syndrome de Guillain-Barré, maladie d'Addison et autres maladies immuno-médiées; l'ostéoporose; les cancers.These drugs find their therapeutic use, especially in the treatment and prevention of neurodegenerative diseases such as Parkinson's disease, Alzheimer's, tauopathies (eg, supranuclear progressive paralysis, fronto-temporal dementia, corticobasal degeneration). Pick's disease); brain trauma such as ischemia and head trauma and epilepsy; psychiatric illnesses such as schizophrenia, depression, substance dependence, attention deficit disorder and hyperactivity disorder; inflammatory diseases of the central nervous system such as multiple sclerosis, encephalitis, myelitis and encephalomyelitis and other inflammatory diseases such as vascular diseases, atherosclerosis, inflammation of the joints, osteoarthritis, rheumatoid arthritis; osteoarthritis, Crohn's disease, ulcerative colitis; allergic inflammatory diseases such as asthma, autoimmune diseases such as type 1 diabetes, lupus, scleroderma, Guillain-Barré syndrome, Addison's disease and other immuno-mediated diseases; osteoporosis; cancers.

Ces composés pourraient être aussi utilisés comme traitement associé à des greffes et/ou transplantations de cellules souches.These compounds could also be used as a treatment associated with stem cell transplants and / or transplants.

Selon un autre de ses aspects, la présente invention concerne des compositions pharmaceutiques comprenant, en tant que principe actif, un composé selon l'invention. Ces compositions pharmaceutiques contiennent une dose efficace d'au moins un composé selon l'invention, ou un sel pharmaceutiquement acceptable, dudit composé, ainsi qu'au moins un excipient pharmaceutiquement acceptable.According to another of its aspects, the present invention relates to pharmaceutical compositions comprising, as active principle, a compound according to the invention. These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt, of said compound, as well as at least one pharmaceutically acceptable excipient.

Lesdits excipients sont choisis selon la forme pharmaceutique et le mode d'administration souhaité, parmi les excipients habituels qui sont connus de l'Homme du métier.Said excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art.

Dans les compositions pharmaceutiques de la présente invention pour l'administration orale, sublinguale, sous-cutanée, intramusculaire, intra-veineuse, topique, locale, intratrachéale, intranasale, transdermique ou rectale, le principe actif de formule (I) ci-dessus, ou son sel, peut être administré sous forme unitaire d'administration, en mélange avec des excipients pharmaceutiques classiques, aux animaux et aux êtres humains pour la prophylaxie ou le traitement des troubles ou des maladies ci-dessus.In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula (I) above, or its salt, may be administered in unit dosage form, in admixture with conventional pharmaceutical excipients, to animals and humans for the prophylaxis or treatment of the above disorders or diseases.

Les formes unitaires d'administration appropriées comprennent les formes par voie orale telles que les comprimés, les gélules molles ou dures, les poudres, les granules et les solutions ou suspensions orales, les formes d'administration sublinguale, buccale, intratrachéale, intraoculaire, intranasale, par inhalation, les formes d'administration topique, transdermique, sous-cutanée, intramusculaire ou intraveineuse, les formes d'administration rectale et les implants. Pour l'application topique, en peut utiliser les composés selon l'invention dans des crèmes, gels, pommades ou lotions.Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal forms of administration. by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, administration forms rectal and implants. For topical application, the compounds according to the invention can be used in creams, gels, ointments or lotions.

A titre d'exemple, une forme unitaire d'administration d'un composé selon l'invention sous forme de comprimé peut comprendre les composants suivants : Composé selon l'invention 50,0 mg Mannitol 223,75 mg Croscarmellose sodique 6,0 mg Amidon de maïs 15,0 mg Hydroxypropyl-méthylcellulose 2,25 mg Stéarate de magnésium 3,0 mg By way of example, a unitary form of administration of a compound according to the invention in tablet form may comprise the following components: Compound according to the invention 50.0 mg mannitol 223.75 mg Croscarmellose sodium 6.0 mg Corn starch 15.0 mg Hydroxypropylmethylcellulose 2.25 mg Magnesium stearate 3.0 mg

Il peut y avoir des cas particuliers où des dosages plus élevés ou plus faibles sont appropriés ; de tels dosages ne sortent pas du cadre de l'invention. Selon la pratique habituelle, le dosage approprié à chaque patient est déterminé par le médecin selon le mode d'administration, le poids et la réponse dudit patient.There may be special cases where higher or lower dosages are appropriate; such dosages are not outside the scope of the invention. According to the usual practice, the dosage appropriate to each patient is determined by the physician according to the mode of administration, the weight and the response of said patient.

La présente invention divulgue également une méthode de traitement des pathologies ci-dessus indiquées qui comprend l'administration, à un patient, d'une dose efficace d'un composé selon l'invention, ou un de ses sels pharmaceutiquement acceptables.The present invention also discloses a method of treating the above-indicated pathologies which comprises administering to a patient an effective dose of a compound of the invention, or a pharmaceutically acceptable salt thereof.

Claims (17)

  1. Compounds of formula (I):
    Figure imgb0018
     in which:
    R represents a hydrogen or halogen atom or a group (C1-C6)alkyl;
    X represents one or more substituents chosen from a hydrogen or halogen atom and a group (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, cyano, hydroxyl or hydroxy(C1-C6)alkyl;
    Y represents a hydrogen or halogen atom or a group (C1-C6)alkyl;
    R1 represents a group NR2R3 or OR4;
    R2 and R3 represent, independently of each other, a hydrogen atom or a group (C1-C6)alkyl, hydroxy(C1-C6)alkyl or oxo(C1-C6)alkyl, or alternatively R2 and R3 form, with the nitrogen atom that bears them, a heterocycle optionally substituted with a group (C1-C6)alkyl, hydroxyl or oxo,
    R4 represents a group (C1-C6)alkyl, hydroxy(C1-C6)alkyl or oxo(C1-C6)alkyl, in the form of base or of acid-addition salt.
  2. Compounds of formula (I) according to Claim 1, characterized in that
    R represents a hydrogen or chlorine atom,
    X represents one or more substituents chosen from a halogen atom and a group (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy or cyano,
    Y represents a hydrogen atom, a halogen atom or a group (C1-C6)alkyl;
    R1 represents a group OR4,
    R4 represents a methyl group, in the form of base or of acid-addition salt.
  3. Compounds of formula (I) according to Claim 1, characterized in that
    R represents a hydrogen or chlorine atom,
    X represents one or more substituents chosen from a chlorine or fluorine atom and a methyl, trifluoromethyl, methoxy, trifluoromethoxy or cyano group,
    Y represents a hydrogen, chlorine or fluorine atom or a methyl group,
    R1 represents a group OR4,
    R4 represents a methyl group, in the form of base or of acid-addition salt.
  4. Compounds of formula (I) according to Claim 1, characterized in that
    R represents a hydrogen or chlorine atom,
    X represents one or more substituents chosen from a halogen atom and a group (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy or cyano,
    Y represents a hydrogen atom, a halogen atom or a group (C1-C6)alkyl;
    R1 represents a group NR2R3,
    R2 and R3 represent, independently of each other, a hydrogen atom or a methyl, ethyl, isopropyl or cyclopropyl group, or alternatively R2 and R3 form, with the nitrogen atom that bears them, a morpholinyl or pyrrolidinyl group optionally substituted with a hydroxyl group, in the form of base or of acid-addition salt.
  5. Compounds of formula (I) according to Claim 1, characterized in that
    R represents a hydrogen or chlorine atom,
    X represents one or more substituents chosen from a chlorine or fluorine atom and a methyl, trifluoromethyl, methoxy, trifluoromethoxy or cyano group,
    Y represents a hydrogen or chlorine atom or a methyl group,
    R1 represents a group NR2R3,
    R2 and R3 represent, independently of each other, a hydrogen atom or a methyl, ethyl, isopropyl or cyclopropyl group, or alternatively R2 and R3 form, with the nitrogen atom that bears them, a morpholinyl or pyrrolidinyl group optionally substituted with a hydroxyl group, in the form of base or of acid-addition salt.
  6. Compounds of formula (I) according to any one of Claims 1 to 5:
    • Methyl 3-[2-(4-chlorophenyl)pyrazolo[1,5-a]pyridin-5-yl]benzoate
    • 3-[2-(4-Chlorophenyl)pyrazolo[1,5-a]pyridin-5-yl]benzamide
    • 3-[2-(4-Chlorophenyl)pyrazolo[1,5-a]pyridin-5-yl]-N,N-dimethylbenzamide
    • 3-[2-(4-Chlorophenyl)pyrazolo[1,5-a]pyridin-5-yl]-N-methylbenzamide
    • Methyl 3-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl]benzoate
    • 3-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl]-N-methylbenzamide
    • 3-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl]-N-isopropylbenzamide
    • 3-[2-(4-Fluorophenyl)pyrzolo[1,5-a]pyridin-5-yl]-N,N-dimethylbenzamide
    • {3-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl]phenyl}morpholin-4-yl-methanone
    • 3-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl]-2,N-dimethylbenzamide
    • 2-Chloro-5-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl]-N-methylbenzamide
    • 4-Chloro-3-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl]-N-methylbenzamide
    • 3-[2-(4-Fluorophenyl}pyrazolo[1,5-a]pyridin-5-yl]-4,N-dimethylbenzamide
    • 2-Fluoro-4-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl]-N-methylbenzamide
    • N-Cyclopropyl-3-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl]benzamide
    • {3-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl]phenyllpyrrolidin-1-ylmethanone
    • 3-[2-(2,6-Difluorophenyl)pyrazolo[1,5-a]pyridin-5-yl-methylbenzamide
    • 3-[2-(2-Fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl]-N-methylbenzamide
    • N-Methyl-3-[2-(4-trifluoromethylphenyl)pyrazolo[1,5-a]pyridin-5-yl]benzamide
    • 4-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl]-N-methylbenzamide
    • 2-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl]-N-methylbenzamide
    • {3-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl]phenyl}-(3-hydroxypyrrolidin-1-yl)methanone
    • 3-[2-(2,4-Difluorophenyl)pyrazolo[1,5-a]pyridin-5-yl]-N-methylbenzamide
    • N-Methyl-3-[2-(4-trifluoromethoxyphenyl)pyrazolo[1,5-a]pyridin-5-yl]benzamide
    • 3-[2-(3,4-Difluorophenyl)pyrazolo[1,5-a]pyrazolo-5-yl]-N-methylbenzamide
    • 3-[2-(3,5-Difluorophenyl)pyrazolo[1,5-a]pyridin-5-yl]-N-methylbenzamide
    • 3-[2-(3-Fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl]-N-methylbenzamide
    • N-Methyl-3-(2-p-tolylpyrazolo[1,5-a]pyridin-5-yl)benzamide
    • 3-[2-(4-Methoxyphenyl)pyrazolo[1,5-a]pyridin-5-yl]-N-methylbenzamide
    • 3-[2-(3,4-Dimethylphenyl)pyrazolo[1,5-a]pyridin-5-yl]-N-methylbenzamide
    • 3-[2-(4-Cyanophenyl)pyrazolo[1,5-a]pyridin-5-yl]-N-methylbenzamide
    • 3-[2-(2,3-Difluorophenyl)pyrazolo[1,5-a]pyridin-5-yl]-N-methylbenzamide
    • N-Methyl-3-(2-o-tolylpyrazolo[1,5-a]pyridin-5-yl)benzamide
    • 3-[3-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl]-N-methylbenzamide
  7. Medicament, characterized in that it comprises a compound of formula (I) according to any one of Claims 1 to 6, or an addition salt of this compound with a pharmaceutically acceptable acid.
  8. Pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to any one of Claims 1 to 6, or a pharmaceutically acceptable salt of this compound, and also at least one pharmaceutically acceptable excipient.
  9. Use of a compound of formula (I) according to any one of Claims 1 to 6, for the preparation of a medicament for treating and preventing neurodegenerative diseases.
  10. Use of a compound of formula (I) according to any one of Claims 1 to 6, for the preparation of a medicament for treating and preventing cerebral trauma and epilepsy.
  11. Use of a compound of formula (I) according to any one of Claims 1 to 6, for the preparation of a medicament for treating and preventing psychiatric diseases.
  12. Use of a compound of formula (I) according to any one of Claims 1 to 6, for the preparation of a medicament for treating and preventing inflammatory diseases.
  13. Use of a compound of formula (I) according to any one of Claims 1 to 6, for the preparation of a medicament for treating and preventing osteoporosis and cancers.
  14. Use of a compound of formula (I) according to any one of Claims 1 to 6, for the preparation of a medicament for treating and preventing Parkinson's disease, Alzheimer's disease, tauopathies and multiple sclerosis.
  15. Use of a compound of formula (I) according to any one of Claims 1 to 6, for the preparation of a medicament for treating and preventing schizophrenia, depression, substance dependency and attention-deficit hyperactivity disorder.
  16. Intermediate compound of formula (VI-1)
    Figure imgb0019
  17. Use of the compound according to Claim 16 for the synthesis of products of general formula (I) according to Claim 1.
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